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Page 2 of 79 DIMTS Registration Review Team

Human Health & Environmental Effects Jenny Tao Nate Mottl Kristin Rury Siroos Mostaghimi Daniel Cherry Jim Breithaupt

Risk Management Lorena Ri vas/Jacqueline Hardy SanYvette Williams Rose KyprianouDocket Number EPA

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Page 3 of 79 TERMS, ABBREVIATIONS AND SYMBOLS

AD Antimicrobials Division A.I. or a.i. active ingredient aPAD a cute p opulation a djusted d ose ASRI a ctivated sludge r espiration i nhibition
atm

- m 3 /mole a tmospher ic pressure

- cubic meter per mole BCF b ioconcentration f actor °C d egrees Celsius CAS Chemical Abstracts Service CFR Code of Federal Regulations CHO Chinese h amster o vary CMA Chemical Manufacturers Association CO 2 c arbon dioxide COC c oncentratio n

- of

- c oncern cPAD c hronic p opulation a djusted d ose DCI data call

- in DOC Dissolved organic carbon EC 50 m edian (or 50 percent) e ffect c oncentration EC 05 5 p ercent e ffect c oncentration ECOTOX ECOTOXicology EDI e stimated daily i ntake EDSP E ndocrine Di sruptor Screening Program E

- FAST Exposure and Fate Assessment Screening Tool EPI Suite Estimation Program Interface Suite EPA Environmental Protection Agency FDA Food and Drug Administration FFDCA Feder al Food, Drug, and Cosmetic Act FIFRA Federal Insecticide, Fungicide, and Rodenticide Act FQPA Food Quality Protection Act FWP Final Work Plan g/mol g rams per mole GLN guideline number HPV h igh production v olume IDS Incident Data System Koc o rganic carbon normalized soil

- water partition coe fficient Kd s oil

- water partition coefficient Kow o ctanol

- water partition coefficient LC 50 m edian (or 50 percent) l ethal c oncentration LD 50 m edian (or 50 percent) l ethal d ose LOAEC l owest

- o bserved

- a dverse

- e ffect

- c oncentration LOEC l owest

- o bserved

- e ffec t

- c oncentration LOAEL lowest

- observed

- adverse

- e ffect

- l evel Log K ow l ogarithm of the octanol

- water partition coefficient
μg m icrogram ml/g m illiliter p er g ram mg/kg m illigram p er k ilogram mg/kg/day m illigram p er k ilogram p er d ay mg/L m illigram p er l ite r mm Hg m illimeter of mercuryDocket Number EPA

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Page 4 of 79 MOE m argin of e xposure MRID Master Record Identification Number MRL m aximum r esidue l imit N/A n ot a pplicable

nm n anometers NOAEC no

- observed

- adverse

- effect

- c oncentration NOAEL n o

- o bserved

- a dverse

- e ffect

- l evel OCSPP Of fice of Chemical Safety and Pollution Prevention OECD Organization for Economic Co

- operation and Development OPP Office of Pesticide Programs PAD p opulation a djusted d ose PAI p ure active i ngredient PDM Probabilistic Dilution Model % p ercent PC Code P esticide Chemical Code PCF p ounds p er c ubic foot pH power of h ydrogen or power of the con centration of the hydrogen ion PHED Pesticide Handler’s Exposure Data PIS primary i rritation s core pKa p ower of the acid dissociation constant or negative base

- 10 logarithm of the acid dissociation constant of a solution ppb p arts p er b illion
ppm p arts p er m illion PWP Preliminary Work Plan QSAR q uantitative s tructure

- a ctivity r elationship RED Rere gistration Eligibility Decision SAR s tructure a ctivity r elatio nship SF s afety f actor SSTS Section Seven Tracking System TEP t ypical e nd

- u se p roduct TGAI t echnical grade active i ngredient TMDL total maximum daily l oads UF uncertainty factor UV/VIS ultraviolet/v isible light a bsorption % w / w p ercent weight per weight. WP w ettable powder WWTPs w astewater treatment plantsDocket Number EPA

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Page 5 of 79 

### Table of Contents 1 Introduction

................................ ................................ ................................ ............................. 7 1.1 Statutory and Regulatory Authority

................................ ................................ ................. 7 1.2 C ase Overview

................................ ................................ ................................ ................. 7 1.3 Chemical Identification and Properties

................................ ................................ ............ 9 1.4 Use/Usa ge Description

................................ ................................ ................................ ... 11 1.4.1 Registrations

................................ ................................ ................................ ........... 11 1.4.2 Summary of Registered Uses

................................ ................................ .................. 11 1.5 Regulatory History

................................ ................................ ................................ ......... 12 1.5.1 Recent/Pending Regulatory Actions

................................ ................................ ....... 12 1.5.2 Toleran ce Information

................................ ................................ ............................ 12 1.6 Incidents

................................ ................................ ................................ ......................... 13 1.6.1 Human Health

................................ ................................ ................................ ......... 13 1.6.2 Ecological

................................ ................................ ................................ ............... 13 2 Anticipated Data Needs

................................ ................................ ................................ ........ 13 3 Human Health Risk Assessment

................................ ................................ ........................... 16 3.1 Existing Toxicological Endpoints

................................ ................................ .................. 16 3.2 Dietary Exposure

................................ ................................ ................................ ............ 18 3.2.1 Food

................................ ................................ ................................ ........................ 18 3.2.2 Drinking Water

................................ ................................ ................................ ....... 21 3.3 Occupational and Residential Exposures

................................ ................................ ....... 21 3.3.1 Occupational Handler Exposure

................................ ................................ ............. 22 3.3.2 Occupational Post

- application Exposure

................................ ................................ 22 3.3.3 Res idential Handler Exposures

................................ ................................ ............... 23 3.3.4 Residential Post

- Application Exposures

................................ ................................ . 23 3.4 Aggregate and Cumulative Exposure

................................ ................................ ............. 24 3.4.1 Aggregate Exposures

................................ ................................ .............................. 24 3.4.2 Cumulative Exposures

................................ ................................ ............................ 24 4 Environmental Risk Assessment

................................ ................................ ........................... 24 4.1 Environmental Fate Assessment

................................ ................................ .................... 25 4.1.1 Waste Water Treatment Plants (WWTP)

................................ ................................ 26 4.1.2 Water Quality

................................ ................................ ................................ .......... 26 4.2 Conceptual Models for Environ mental Exposure Pathways

................................ .......... 26 4.3 Ecological Effects Assessment

................................ ................................ ....................... 27 4.3.1 Mechanism of Action

................................ ................................ .............................. 27 4.3.2 Measures of Effect (Ecotoxicology Endpoints)

................................ ...................... 27 4.4 Exposure Analysis Plan

................................ ................................ ................................ .. 28 4.4.1 Aquatic and Terrestrial Wildlife Exposure Estimates

................................ ............ 28 4.4.2 Screening Level Down

- the

- Drain Analysis

................................ ............................ 28 4.5 Effects Analysis Plan

................................ ................................ ................................ ..... 30 5 Endocrine Disruptor Screening Program (EDSP)

................................ ................................ . 30 6 Optional Label Changes

................................ ................................ ................................ ........ 31 7 Guidance for Commenters

................................ ................................ ................................ .... 31 7.1 Preliminary Work Plan

................................ ................................ ................................ ... 31 7.1.1 Trade Irritants

................................ ................................ ................................ .......... 31 7.1.2 Water Quality

................................ ................................ ................................ .......... 31Docket Number EPA

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Page 6 of 79 7.1.3 Environmental Justice

................................ ................................ ............................. 32 7.1.4 Structure Activity Relationships

................................ ................................ ............. 32 7.1.5 Additional Information

................................ ................................ ........................... 33 8 Next Steps

................................ ................................ ................................ ............................. 33 9 References

................................ ................................ ................................ ............................. 34

Appendix A T oxicology Profile

................................ ................................ ............................... 35 Appendix B Environmental Fate

................................ ................................ ............................. 64 Appendix C Ecotoxicology Profile

................................ ................................ .......................... 71 Appendix D Screeni ng Level Down

- the

- Drain Analysis

................................ ........................ 76 Appendix E Product Chemistry

................................ ................................ ............................... 77

List of Tables Table 1

– Summary of Anticipated Risk Assessments and Data Needs for Registration Review: DIMTS

................................ ................................ ................................ ................................ ............ 8 Table 2

– Anticipated Registration Review Schedule

................................ ................................ .... 8 Table 3

– Chemical Identification of DIMTS

................................ ................................ ................. 9 Table 4

– P hysical

- Chemical and Environmental Fate Properties for Parent DIMTS

................... 9 Table 5

– Physical

- Chemical and Environmental Fate Properties for Monoiodo

- p

methyltolylsulfone (MIMPTS), methyl

- p

- tolylsulfone (MPTS), and p

- toluene sulfonic acid (PTSOA) Degradates

................................ ................................ ................................ .................... 10 Table 6

– Summary of Diiodomethyl p

- tolyl sulfone (DIMTS) Registered Uses

........................ 11 Table 7

– Studies Anticipated as Needed for the Registration Review of DIMTS

...................... 14 Table 8

– Data Needs Required by the February 24, 2010 Data Call

- In for the DIMTS RED

.... 15 Table 9

– Existing Toxicological Endpoints for DIMTS

................................ .............................. 16 Table 10

– Occupational Handler Exposure Scenarios for DIMTS

................................ ............. 22 Table 11

– Residential Handler Exposure Scenarios for DIMTS

................................ ................. 23 Table 12

– Residential Post

- Application Exposure Scenarios for DIMTS

................................ ... 23 Table 13

– Selected Ecological Effects Endpoints fo r Risk Assessment of DIMTS

.................... 27 Table 14

– Summary of Screening Level Down

- the

- Drain Analysis Results for Aquatic Organisms

................................ ................................ ................................ ................................ ..... 29Docket Number EPA

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Page 7 of 79 

## 1 Introduction

This document is the United States Environmental Protection Agency ’s ( USEPA, EPA or “the

a gency ”) Preliminary Work Plan (PWP) for Diiodomethyl p

- tolyl sulfone (DIMTS)

, formerly referred to as Amical 48 . The PWP document explains what EPA's Office of Pesticide Programs (OPP) knows about DIMTS , highlighting anticipated data and assessment needs, identifying the types of information that would be especially useful to the a gency in conducting th e review, and providing an anticipated timeline for completing the DIMTS review.

The registration review process was designed to include a public participation component to solicit input from interested stakeholders. The a gency intends, by sharing this inf ormation in the docket, to inform the public of what it knows about DIMTS and what types of new data or other information would be helpful for the a gency to receive as it moves toward a decision on DIMTS

. The a gency encourages all interested stakeholders t o review the PWP and to provide comments and additional information that will help the a gency ’s decision

- making process for this chemical.



## 1.1 Statutory and Regulatory Authority
The Food Quality Protection Act (FQPA) of 1996 mandated a registration review pro gram. All pesticides distributed or sold in the United States generally must be registered by the USEPA based on scientific data showing that they will not cause unreasonable risks to human health or the environment when used as directed on product labelin g. The registration review program is intended to make sure that, as the ability to assess risk evolves and as policies and practices change, all registered pesticides continue to meet the statutory standard of no unreasonable adverse effects to human heal th or the environment. Changes in science, public policy, and pesticide use practices will occur over time. Through the registration review program, the a gency periodically reevaluates pesticides to make sure that as change occurs, products in the marketpl ace can be used safely. Information on this program is provided at http://www2.epa.gov/pesticide

- reevaluation

.
The a gency is implementing the registration review program pursuant to Section 3(g) of the Federal Insecticide, Fungicide, and Rodenticide Act (F IFRA) and will review each registered pesticide every 15 years to determine whether it continues to meet the FIFRA standard for registration. The regulations governing registration review begin at 40 CF R 155.40. The a gency will consider benefits informatio n and data as required by FIFRA. The public phase of registration review begins when the initial docket is opened for each case. The docket is the
agency ’s opportunity to state what it knows about the pesticide and what additional risk analyses and data or information it believes are needed to make a registration review decision. After reviewing and responding to comments and data received in the docket during this initial comment period, the agency will develop and commit to a F inal W ork P lan (FWP) and
ant icipated schedule for the DIMTS case

. 

## 1.2 Case Overview

The docket for DIMTS ( case 4009) has been established at http://www.regulations.gov in docket number EPA

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- 0264

. Documents associated with this regist ration review can beDocket Number EPA

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Page 8 of 79 viewed in this docket. Tables 1

- 2 b elow summar ize the issues relevant to this registration review

case and the anticipated registration review schedule

.
Table 1

– Summary of Anticipated Risk Assessments and Data Needs for Registration Review : DIMTS

Risk Assessment Assessment Necessary to

Support Registration Review Date of Most Recent Assessment Type of Assessment

Required (New/Updated) Data Anticipated as Needed ( See Table 7 for detail s )

Dietary (food) Yes 3/ 28/2008 (RED) Updated Toxicology and Residue Data ( Table 7 )

Dietary (drinking water) Yes N/A New Environmental Fate Data ( Table 7 ) Occupational Handler Yes 3/28/ 20 08 Updated ( Table 7 ) Occupational Post

Application Exposure No 3/28/ 20 08 None None

Residential Handler Yes 3/28/ 20 08 Updated ( Table 7 )

Resident i al Post Application

- Incidental Oral and Dermal Yes 3/28/ 20 08 Updated ( Table 7 )

Resident i al Post Application

- Inhalation No 3/28/ 20 08 None None

Aggregate Yes 3/28/ 20 08 Updated ( Tabl e 7 )

Cumulative No 3/28/ 20 08 None None

Tolerance Review No N/A None None

Ecological Yes 11/1/2007 Updated L eaching

- adsorption

- desorption and Ecotoxicity data N/A = Not applicable * Table 1 is a summary of the anticipated risk assessments and dat a needs for Registration Review. For data called in through the post

Reregistration Eligibility Decision ( RED ) Data Call

- In ( DCI ) , se e Table 8 of this PWP

.

Table 2

– Anticipated Registration Review Schedule
Anticipated Activity Ta rget Date * Completion Date Phase 1: Opening the Docket Open Docket and 60

- Day Comment Period for Preli minary Work Plan 2015

- 09 2015

- 09 Close Public Comment Period 2015

- 11 2015

- 11 Phase 2: Case Development

Issue Final Work Plan 2016

- 03

Issue Data Call

- In (DCI) 2017

- 03

Receive Data to be Considered in Risk Assessment 2019

- 03

Open 30

- Day Public Comment Period for Preliminary Risk Assessment(s) 2020

- 09

Close Public Comment Period 2020

- 10Docket Number EPA

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Page 9 of 79 Phase 3: Registration Review Decision and Impleme ntation
Open 60

- Day Public Comment Period for Pro posed Decision 2021

- 03

Close Public Comment Period 2021

- 05

Issue Final Decision 2021

- 09

Begin Post

- Decision Follow

- up 2021
Total (years) 6

* The anticipated schedule will be revised as necessary ( e.g ., need arising under the Endocrine Disruptor Screening Program with respect to the active ingredients in this case).


## 1.3 Chemical Identification and Properties

Table 3 presents the active ingredient to be assesse d in case 4009 : DIMTS (PC Code 101002).

Table 3

– Chemical Identification of DIMTS

Chemical Name DIMTS Reference/Comments
PC Code 101002 N/A
CAS Number 20018

- 09

- 1 EPI

- WEB 4.11 Smiles code O=S(=O)(c(ccc(c1)C)c1)C(I)I EPI

- WEB 4.1 1 Molecular Formula C 8 H 8 I 2 O 2 S EPI

- WEB 4.11 Molecular Weight (grams/mole) 422.02 EPI

- WEB 4.11

Molecular Structure N/A

The p hysical chemistry information for parent DIMTS relevant to risk assessment is summarized in Table 4 , while the p hysical chemistr y information for the degradates m onoiodo

- p

methyltolylsulfone (MIM P TS , parent compound minus one iodo group) , methyl

- p

- tolylsulfone (MPTS , parent compound minus both iodo groups ) and p

- toluene sulfonic acid (PTSOA , parent compound minus both iodo groups and a methyl group with added hydroxyl group ) are summarized in Table 5. Further information on p hysical chemistry is located in Appendix E.

Table 4

– Physical

- Chemical and Environmental Fate Properties for Parent DIMTS

Guideline No. P arameter DIMTS Reference (MRID unless specified) Comments

830.7050 UV/Visible Absorption Max sorption at 288 nm, some tailing through 409 nm 47234003

830.7370 Dissociation c onstant (pKa) Not applicable 48511201Docket Number EPA

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Page 10 of 79 Guideline No. P arameter DIMTS Reference (MRID unless specified) Comments

830.7550 Octanol

- water partition co efficient at 25 o C (Log K ow ) 2.66 42177202

830.7840 Solubility in water (mg/L) <2 47373801 830.7950 Vapor pressure (mmHg) 4.9 x 10

- 7 47373801

None Henry's l aw c onstant at 25 o C (atm

- m 3 /mol) 1.4 x 10

- 7 Calculated

atm

- m 3 /mol = atmosphere cubic meter per mole; o C = degrees Celsius; mg/L = milligrams per liter; mmHg = millimeters of mercury

.
Table 5

– Physical

- Chemical and Environmental Fate Properties for Monoiodo

- p methyltolylsulfone (MIM P TS), methyl

- p - tolylsulfone (MPTS), and p - toluene sulfonic acid (PTSOA) Degradates
Guideline No. Parameter Monoiodo

- p methyltolylsulfone (MIM P TS) Methyl

- p - tolyl sulfone ( MPTS ) P

- toluene sulfonic acid (PTSOA) Reference (MRID unless specified) Comments

None Structure None

None Description Parent minus 1 iodine Parent minus two iodines Hydroxylated,

once

- demethylated MPTS None

None PC Code None None None Not applicable

None CAS No. 37891

- 96

- 6 59203

- 01

- 9 104

- 15

- 4 Dow MSDS (MIM P TS) Chemical Book ( MPTS )

None Smiles code O=S(=O)(c(ccc(c1)C) c1)C(I) O=S(=O)(c(ccc(c1)C) c1)C O=S(O)(=O)(c(ccc( c1)C)c1) EPI

- WEB 4.11

None Molecular formula C 8 H 9 IO 2 S C 8 H 10 O 2 S C 7 H 8 O 3 S EPI

- Web 4.11

None Molecular weight 296.12 170.23 172.20 EPI

- WEB 4.11

830.7050 UV/Visible Absorption No data No data No data Similar to parent

830.7370 Dissociation constant (pKa) Not applicable Not applicable Not applicable Similar to p arent

830.7550 Octanol

- water partition coefficient at 25 o C (Log K ow ) 2.3 1.94

- 0.62 47338402 (MIM P TS and MPTS) EPI

- WEB 4.11 (PTSOA)

830.7840 Solubi lity in water (mg/L) 140.4 1

, 352 6.2 x 10 5 47338402 (MIM P TS and MPTS) EPI

- WEB 4.11 (PTSOA) O
S
O H 3 C I O
S O H

3 C

C H

3Docket Number EPA

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Page 11 of 79 Guideline No. Parameter Monoiodo

- p methyltolylsulfone (MIM P TS) Methyl

- p - tolyl sulfone ( MPTS ) P

- toluene sulfonic acid (PTSOA) Reference (MRID unless specified) Comments

830.7950 Vapor pressure (mmHg) 2.3 x 10

- 5 2 x 10

- 3 2.9 x 10

- 6 EPI

- WEB 4.11

None Henry's law constant at 25

o C (atm

m 3 /mol) 6.4 x 10

- 8 3.3 x 10

- 7 1.1 x 10

- 12 Calcul ated

atm

- m 3 /mol = atmosphere cubic meter per mole; o C = degrees Celsius; mg/L = milligrams per liter; mmHg = millimeters of mercury.



## 1.4 Use/Usage Description

1.4.1 Registrations

There are seven EPA

- registered products that contain diiodomethyl p

- tolyl sulfone a s a n active ingredient (a.i.). The percent a.i. ranges from 0.95 to 95 percent, and the formulations include flowable and soluble concentrates, liquids

, and wettable powder. Some of these registered products also contain other active ingredients such as propi conazole, 3

- iodo

- propyl butyl carbamate (IDPC), and chlorothalonil.



### 1.4.2 Summary of Registered Uses

A summary of the registered uses of DIMTS that will be assessed in this registration review is shown in Table 6

. DIMTS can be applied by the following applicati on methods: roll coating, liquid pour, liquid pump

, solid pour, solid place, sapstain spray and dip, airless sprayer (paints and stains) , paint brush/roller (paints and stains) and high pressure spray er (treated wood)

.
Table 6

– Su mmary of Diiodomethyl p

- tolyl sulfone (D I MTS) Registered Uses

Uses Application Method Application Rate
Material Preservatives
Paints Liquid Pour

57 00 ppm Liquid Pump Roll Coating

Paintbrush/Roller

2850 ppm

Airless Sprayer

Solid Pour

Solid Place

Adhesives, caulks, dispersions, and sealants Solid Pour 2358 ppm Solid Place Liquid Pour 1650 ppm Liquid Pump
Pigment Dispersions, Inks and Extender Slurries Liquid Pour 1425 ppm Liquid PumpDocket Number EPA

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Page 12 of 79 Uses Application Method Application Rate

Rubber, Plastics and Vinyl Products Liquid Pour 7600 ppm Liquid Pump 7600 ppm

Paper Production Liquid Pour 3156 ppm Liquid Pump 3156 ppm

Solid Pour 3156 ppm

Solid Place 3156 ppm

Hides and Leather Liquid Pour 2650 ppm Liquid Pump 2650 ppm

Solid Pour 3000 ppm

Solid Place 3000 ppm

T extiles Liquid Pour 5 0 00 ppm Liquid Pump 5 0 00 ppm

Solid Pour 4750 ppm

Solid Place 4750 ppm
Wood Preservatives
Forest Products Pressure Treatment 0.0065 lb ai/cu. ft

Forest Products High Pressure Spray 400 ppm

Forest Products Spray Sapstain 40 ppm Forest Products Dip



## 1.5 Regulatory Histor y

DIMTS was first registered as an active ingredient on September 17, 1980. A Reregistration Eligibility Decision (RED) was done in 2008. Currently, there are seven active registrations (EPA Reg. Nos. 464

- 670, 46 4

- 672, 464

- 673, 60061

- 112, 60061

- 126, 60061

- 127, and 74075

- 1) for products containing DIMTS as an algaecide, bactericide, and fungicide. It is used as a materials preservative in paints, air duct coatings, fire

- retardant coatings, pigment dispersions, inks , emulsions, extender slurries, adhesives, caulks, sealants, rubbers, plastic, textiles, leather, paper production to protect pulp and slurries, paper/paperboard, and wetlap. It is also used as a wood preservative.



### 1.5.1 Recent/Pending Regulatory Actions

There a re no recent or pending regulatory actions for DIMTS.



### 1.5.2 Tolerance Information

For DIMTS , there are no EPA registered direct food contact uses. However t here are multiple registered labeled uses that could result in indirect food contact including under 21 CF R parts 175, 176 and 177 : (1) use in caulks and sealants (adhesives) , (2) use in rubber and plastic products (polymers) , and (3) use as a mold preventer during paper production and paper storageDocket Number EPA

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Page 13 of 79 (paper slimicides)

. There is a Fo od and Drug Administration ( FDA ) food additive regulation under CFR 176.300, which allows 0.2 lb DIMTS per ton of dry weight fiber for paper and paper board. This food additive regulation in relation to currently registered uses for DIMTS is discussed further in Section 3.2.1 of this document.

EPA has not established tolerances or exemptions for tolerances in/on any raw agricultural commodities or processed food and feed products under the Federal Food, Drug and Cosmetic Act (FFDCA) Section 408.



## 1.6 Incidents

1.6.1 Human Health

No DIMTS human poisoning incidents have been reported in OPP’s Incident Data System (IDS) since 1992 based on the search conducted on June 25, 2015

.


### 1.6.2 Ecological

No DIMTS ecological incidents have been reported in IDS since 1992 based on the search conducted on June 23, 2 015.


## 2 A nticipated Data Needs

Several studies were already required from the assessment of DIMTS in the 2008 RED. In addition to the already

- required RED DCI data, the following studies as listed in Table 7 are anticipated to be needed for the registration review of DIMTS

. Table 8 outlines the data requirements required by the post

- RED DCI issued on February 24, 2010. The agency anticipates reviewing any data received in response to the post

- RED DCI as well as data requested for this registration review prio r to conducting the registration review risk assessments for DIMTS

.Docket Number EPA

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Page 14 of 79 Table 7

– Studies Anticipated as Needed for the Registration Review of DIMTS

GLN Study Name Test Substance Time Frame (Measured in months from DCI Receipt) Risk Assessment(s) Data Will Support Use Site(s) Triggering Anticipated Data

Requirement Applicable Exposure Scenario

835.1230 Leaching

- adsorption

desorption TGAI, MIMPTS, MPTS 12 Ecological All Ecological exposure and drinking water

850.1075 Acute estuarin e/marine fish toxicity TGAI 12 Ecological All Ecological exposure

850.1035 Mysid acute toxicity test TGAI 12 Ecological All Ecological exposure 850.1025 Oyster acute toxicity test TGAI 12 Ecological All Ecological exposure

850.1300 Aquatic invertebrate life cycle MIMPTS 12 Ecological All Ecological exposure

850.1400 Fish early

- life stage MIMPTS 12 Ecological All Ecological exposure 850.3020 Honeybee acute contact TGAI 12 Ecological All Ecological exposure

850.4400 Aquatic vascular plant growth TEP 12 Ecological All Ecological exposure

850.4500 Aquatic plant growth (algal) 1 TEP 12 Ecological All Ecological exposure

850.4550 Cyanobacteria toxicity 1 TEP 12 Ecological All Ecological exposure 860.1340 Residue analytical method TGAI 12 Human Health All Human health exposure 860.1380 Storage stability data TGAI 12 Human Health All Human health exposure

870.4300 Combined Chronic Toxicity/Carcinogenicity TGAI 24 Human Health All Human health exposure

870.6200 Neurotoxicity screening battery 2 TGAI 24 Hum an Health All Human health exposure

870.7800 Immunotoxicity 3 TGAI 12 Human Health All Human health exposure

None Migration Study 4 EP 12 Human Health Paper production, plastics, adhesives and sealants Human health exposure

1 In a Federal Register Notic e dated June 27, 2012, EPA split the Public Draft OPPTS 850.5400 test guideline into two test guidelines: OCSPP 850.4500 and OCSPP 850.4550. See “Final Test Guidelines; OCSPP 850 Series; Notice of Availability” 77 FR 38282, June 27, 2012. http://www.regula tions.gov/#!documentDetail;D=EPA

- HQ

- OPPT

- 2009

- 0154

- 0028.

2 Acute (study due 12 months after receipt of DCI) and subchronic (study due 24 months after receipt of DCI) neurotoxicity studies ar e anticipated to be required. A protocol should be submitted to th e agency for review prior to conducting the neurotoxicity studies.
3 All 90

- day subchronic studies in the rodent can be designed to simultaneously fulfill the requirements of the 90

- day immunotoxicity studies by adding separate groups of animals for testin g of immunotoxicity parameters

.Docket Number EPA

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Page 15 of 79 4 Based on the results of the screening

- level dietary (food) analysis for paper mold inhibition, paper plant storage and preservation, and food

- contact polymers using label

- provided inputs resulting in risks above the agency ’s level of concern for some population subgroups

, the migration stud y is expected to be required and p ro tocols must be approved by the a gency prior to the initiation of the study.

Table 8

– Data Needs Required by the February 24, 2010 Data Call

- In for the D I MTS RE D

GLN Study Name Status

875.1100 Dermal exposure

-- outdoor

Study not received 875.1300 Inhalation exposure

- outdoor

875.1600 Application exposure monitoring data reporting Waived

875.2300 Indoor Surface Residue Dissi pation Study not received

875.1700 Product Use

Acceptable 875.2700 Product Use

875.2800 Description of Product UseDocket Number EPA

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Page 16 of 79 

## 3 Human Health Risk Assessment

The a gency anticipates the need to conduct a human health risk assessment for DIMTS

. The
agency will e valuate the additional data required by the post

- RED DCI. Additionally, the a gency anticipates the need to require additional data for the registration review of DIMTS , based on the currently registered use s. These additional studies include mammalian toxi city data from a combined chronic toxicity /carcinogenicity study, an immunotoxicity study and neurotoxicity screening battery , and all applicable exposure studies. A detailed description of the available toxicity studies is provided in Appendix A.



## 3.1 Existing Toxicological Endpoints

The ag ency anticipates the need to revise the existing toxicological endpoints from the 2008 RED , shown in Table 9
, as part of registration review. All available information

, including existing toxicology studies and valid scientif ic literature, will be considered in establishing the toxicology endpoints to be used in the registration review risk assessment.

Table 9

– Existing Toxicological Endpoints for DIMTS

Exposure Scenario Dose Used in Risk Assessment

( mg/kg/day) Target MOE, UF, Special FQPA SF, for Risk Assessment Study and Toxicological Effects

Dietary Risk Assessments Acute Dietary (All populations) No appropriate endpoint can be selected for acute RfD.

Chronic Dietary (All populations) N OAEL = 2 UF = 1000 (10x for inter

species extrapolation, 10x for intra

- species variation, and 10x for lack of chronic and cancer data) 90

- Day Oral Toxicity Study in Dogs (MRIDs 42054403 & 43246402)

LOAEL = 2 mg/kg/day, based on histopathologic changes i n the thyroid glands (degeneration [mineralization within colloid clumping of sloughed follicular cells and colloid depletion]) in the mid

and high

- dose males and females, salivary gland (sialadenitis [ducted and periductal inflammation]) and gastrointest inal (GI) tract (hemorrhagic gastritis, necrosis).
cRfD = 0.0 02 mg/kg/day

Non

- Dietary Risk Assessments

Incidental Oral Short

- Term (1

- 30days) NOAEL maternal = 4 UF = 100 (10x for inter

species extrapolation, 10x for intra

- species variation) Develop mental Toxicity in Rabbits (MRID s 42243801/43246404 )

LOAEL = 15 mg/kg/day, based on clinical signs, reduced body weight gain and food consumption.Docket Number EPA

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Exposure Scenario Dose Used in Risk Assessment

( mg/kg/day) Target MOE, UF, Special FQPA SF, for Risk Assessment Study and Toxicological Effects

Incidental Oral Intermediate

Term (1

- 6 months) N OAEL = 2 UF = 1 00 (10x for inter

species extrapolation, 10x for intra

- species variation) 90

- Day Oral Toxicity Study in Dogs (MRIDs 42054403 / 43246402)

L OAEL = 10 mg/kg/day, based on histopathological changes observed in the thyroid glands ( deg eneration of the thyroid gland [ mineralization within colloid clum ping of sloughed follicular cells and colloid depletion ] ), salivary gland ( Sialadenitis [ ductal and periductal inflammation of the salivar y gland]) and gastrointestinal (GI) tract ( hemorrhagic gastritis, necrosis of the small intestine and keratitis )

. Der mal Absorption Factor 12% (based on a pharmacokinetics and metabolism study in rats (MRID 47076641)

Dermal Short

- Term (1

- 30 days) NOAEL maternal = 4 UF = 100 (10x for inter

species extrapolation, 10x for intra

- species variation) Developmental Toxicity i n Rabbits (MRID s 42243801/43246404 )

LOAEL = 15 mg/kg/day, based on clinical signs, reduced body weight gain and food consumption.
Dermal Intermediate

Term (1

- 6 months) N OAEL = 2 MOE = 1 00 (10x for inter

species extrapolation, 10x for intra

- species vari ation) 90

- Day Oral Toxicity Study in Dogs (MRIDs 42054403 / 43246402)

LOAEL = 10 mg/kg/day, based on histopathological changes observed in the thyroid glands ( deg eneration of the thyroid gland [ mineralization within colloid clumping of sloughed follicula r cells and colloid depletion ] ), salivary gland ( Sialadenitis [ ductal and periductal inflammation of the salivar y gland]) and gastrointestinal (GI) tract ( hemorrhagic gastritis, necrosis of the small intestine and keratitis )

.Docket Number EPA

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Exposure Scenario Dose Used in Risk Assessment

( mg/kg/day) Target MOE, UF, Special FQPA SF, for Risk Assessment Study and Toxicological Effects

Dermal Long

- Term (> 6 months) N OAEL = 2 MOE = 100 0 (10x for inter

species extrapolation, 10x for intra

- species variation, 10 x for lack of chronic and

cancer and reproductive data) 90

- Day Oral Toxicity Study in Dogs (MRIDs 42054403 / 43246402)

LOAEL = 10 mg/kg/day, based on histopat hological changes observed in the thyroid glands ( deg eneration of the thyroid gland [ mineralization within colloid clumping of sloughed follicular cells and colloid depletion ] ), salivary gland ( Sialadenitis [ ductal and periductal inflammation of the saliva r y gland]) and gastrointestinal (GI) tract ( hemorrhagic gastritis, necrosis of the small intestine and keratitis )

. Inhalation (All Durations) N OAEL = 2 MOE = 1 000 (10x for inter

species extrapolation, 10x for intra

- species variation, 1 0x for route

- to

- rou te extrapolation) 90

- Day Oral Toxicity Study in Dogs (MRIDs 42054403 & 43246402)

LOAEL = 10 mg/kg/day, based on histopathological changes observed in the thyroid glands ( deg eneration of the thyroid gland [ mineralization within colloid clumping of sl oughed follicular cells and colloid depletion ] ), salivary gland ( Sialadenitis [ ductal and periductal inflammation of the salivar y gland]) and gastrointestinal (GI) tract ( hemorrhagic gastritis, necrosis of the small intestine and keratitis )

. Cancer (oral, dermal, inhalation) No carcinogenicity data available for DIMTS. This study is anticipated to be required.



## 3.2 Dietary Exposure
The agency anticipates the need to conduct a dietary exposure ( food and drinking water ) assessment to support registration review of DIMTS since there are multiple labeled uses that could result in indirect food contact and the potential for entering surface water and

, therefore, dietary exposure ( food and drinking water ) to DIMTS

.


### 3.2.1 Food The agency anticipates the need to conduct di etary (food) exposure assessments as part of the registration review process to update the previously conducted dietary (food) exposure assessments in the 2008 RED. There are multiple labeled uses that could result in indirect food contact, and

, therefore , dietary exposure to DIMTS . The registered uses of DIMTS (EPA Reg. Nos. 464

- 670, 464

- 672, and 464

- 673) that may result in dietary exposure include: (1) use inDocket Number EPA

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Page 19 of 79 caulks and sealants, (2) use in rubber and plastic products, and (3) use as a mold preventer du ring paper production and paper storage.

Currently, the label statement on EPA Reg. No. 464

- 670 reads “This product is not cleared for use in the manufacture of paper and paperboard products that come in contact with food

. ” However, this registrant indic ated they plan to submit a label change amendment and other information in order to a llow food contact use.

A screening

- level (food only) analysis was conducted using established toxicological points of departure (PODs). Each end

- use product results in d ifferent screening

- level inputs and analysis results. There are no effects attributable to a single dose for DIMTS ; therefore an acute population adjust dose was not established, and an acute dietary exposure assessment was not conducted. However, the chro nic population adjusted dose (cPAD) is 0.002 mg/kg/day for DIMTS

. Additional toxicity and residue chemistry data are anticipated to be required based on the result of the screening

- level analys e s.

Dietary Exposure Assessment

– Paper Production

Three end

- u se product labels could result in indirect food contact to DIMTS : EPA Reg. Nos. 464

- 670, 464

- 672, and 464

- 673. The results have been presented here for the three products for both mold inhibition during paper production and for use in paper plant storage.

Paper Mold Inhibition D uring Production

For the use of DIMTS to prevent mold during paper production, the screening

- level dietary risk assessment indicates that chronic dietary (food only) exposure and risk estimates exceed the level of concern (LOC) [ i.e., >100% of the PAD] for some sub

- populations for all the registered end

- use products.

For the use of DIMTS to prevent mold during paper production, and assuming a food contact surface area of 2000 cm 2 , the screening

- level model for paper productio n results in a total estimated daily dietary intake of DIMTS less than 200 ppb for all three EPA Reg. No s . 464

- 673, 464

- 672 and 464

- 670.

Mold Inhibition During Paper Plant Storage

DIMTS is approved for use in preserving finished paper or paper plant pul p, alum, broke, polymers, defoamers, emulsions, adhesives, paper mill coatings, pigments, and slurries. For these uses of DIMTS, the screening level dietary exposure analysis indicates that the chronic dietary (food only) exposure and risk estimates excee d the level of concern (LOC) [i.e., >100% of the PAD] for all population subgroups and all EPA registered end

- use products.

For the use of DIMTS to prevent mold during paper plant preservation, and assuming a food contact surface area of 2000 cm 2 , the sc reening

- level model for paper production results in a total estimated daily dietary intake of DIMTS greater than 200 ppb for all population subgroups and registered labels; EPA Reg. Nos. 464

- 673, 464

- 672 and 464

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– Paper P roduction Using FDA Food Additive Regulation Level

The concentration s listed on EPA Reg. No s . 464

- 673, 464

- 672 and 464

- 670 are greater than the currently established FDA food additive regulation under CFR 176.300, which only allows 0.2 lb DIMTS per ton of dry weight fiber. Using the assumption of 0.2 lb DIMTS per ton of dry weight fiber, the screening

- level dietary exposure analysis for paper production indicates that the chronic dietary (food only) risk estimates do not exceed the level of concern (LOC) [ i.e., < 100% of the PAD] for all population subgroups. Furthermore, using the FDA Food Additive Regulation Level for DIMTS and assuming a food contact surface area of 2000 cm 2 , the screening

- level model for paper production results in a total estimated da ily dietary intake (EDI) of DIMTS less than 200 ppb for all population subgroups. If the registered DIMTS labels intend to treat paper that may contact food, the labels should be revised to comply with the FDA food additive regulation level of 0.2 lb a

. i

. per ton of dry weight fiber. If labels are not changed before the risk assessment for this registration review , the dietary assessment will be done using 395 ppm listed on the EPA labels.

Dietary Exposure Assessment

– Adhesives

Two products containing D IMTS allow for use in adhesives and sealants; EPA Reg. Nos. 464

- 670 and 464

- 673. Use of DIMTS in sealants used in food packaging may result in DIMTS migrating into food i ndirectly. Therefore, a screening

- level analysis was completed for DIMTS

. The screeni ng

- level assessment was based on the FDA guidance and assumed that a maximum of

seven ppb DIMTS may migrate from the food packaging adhesive into the food; which is a conservative estimate. Using these assumptions, the screening

- level dietary exposure anal ysis for DIMTS in food

- contact adhesives indicates that the chronic dietary (food only) risk estimates do not exceed the level of concern (LOC) [i.e., < 100% of the PAD] for all population subgroups.

Furthermore, the use of DIMTS in food contact adhesive s and assuming a food contact surface area of 2000 cm 2 , the screening

- level model for adhesives results in a total estimated daily dietary intake (EDI) of DIMTS less than 200 ppb for all population subgroups and registered labels.

Dietary Exposure Assess ment

– Polymers

EPA Reg. No. 464

- 670 allows for use of DIMTS in plastic products that may contact food. Therefore, a screening

- level analysis was completed for DIMTS in polymers

. The assessment was conducted using the screening

- level FDA model for food c ontact (hard surfaces) in commercial areas since no chemical

- specific information on density was available. Additionally, the screening

- level assessment assumed that 100% of the DIMTS residues in the plastics will migrate to food and a food contact surface of 4000 cm 2

, which are conservative assumptions. The assessment was based on the registered product concentration of 0.8% DIMTS

. Using these assumptions, the screening

- level dietary exposure analysis for DIMTS in food

- contact plastics indicates that the chronic dietary (food only) risk estimates exceed the level of concern (LOC) [i.e., > 100% of the PAD] for all population subgroups.Docket Number EPA

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Page 21 of 79 Furthermore, the use of DIMTS in food contact polymers and assuming a food contact surface area of 4000 cm 2 , the screenin g

- level model for plastics results in a total estimated daily dietary intake (EDI) of DIMTS greater than 200 ppb.

Conclusions & Data Requirements

The results of the screening

- level analysis for paper mold inhibition, paper plant storage and preservation, a nd food

- contact polymers using label

- provided inputs result in risks above the

a gency’s level of concern for some population subgroups. Additional residue data , including migration studies, residue analytical method for data collection (Guideline 860.1340 ), and storage stability studies (860.1380), are required because the level of concern is exceeded, per 40 CFR §158

. 2290. The labeled uses may need to be removed or revised during Registration Review if additional refinement data are not available for the r isk assessment

. Additionally, the total daily dietary intake for chronic exposures for paper plant preservation and polymers is > 200 ppb for the US population and /or some population subgroups. Therefore,

u nder 40CFR §158.2230

, a total daily dietary inta ke greater than 200 ppb trigger s toxicity data that should be submitted to the a gency.



### 3.2.2 Drinking Water

DIMTS is also registered for use as a fungicide to control mold and sapstain fungi that cause discoloration and staining of freshly sawn lumber. It can al so be applied to dimensional lumber, logs, plywood, Oriented Strand Board (OSB) and particle board to prevent surface mold growth. T here are uncertainties with respect to DIMTS as well as its degradates entering drinking water based on the use patterns

, th e potential for exposure to surface water during manufacturing for the use as a materials preservative, and leaching of DIMTS from treated wood demonstrated in the available data

. The agency has not previously conducted a drinking water assess m e nt for DIMT S and its degradates

. Based on the registered uses

, however, the agency can not rule out the potential for exposure of humans to the parent DIMTS and/or its degradates in drinking water

. Leaching of DIMTS from treated wood was demonstrated (MRID 47375907 )

, and there is the potential for exposure to surface water during manufacturing for the use as a materials preservative. In addition, based on the water solubility values of parent DIMTS in Table 4 and the degradation products in Table 5 and observations in the anaerobic aquatic metabolism study (MRID 42177201)

, most environmental residues of DIMTS are expected to partition to water in the presence of soil and sediment. Moreover, the agency does not have adequate fate data on sorption of parent compound and its degradation products to determine the potential for contamination of drinking water. These fate data are anticipated to be required during registration review

, as noted in Table 7 of this PWP

. These data will be use d to determine whether and to what e xtent DIMTS and its degradates pass through the WWTP that may result in human dietary exposure through drinking water which may trigger a drinking water assessment.



## 3.3 Occupational and Residential ExposuresDocket Number EPA

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Page 22 of 79 The agency anticipates the need to update the occupa tional and residential exposure (ORE) assessment which was originally performed for the 2008 RED. The earlier ORE assessment from the RED will need to be revised to incorporate any revised toxicology endpoint selections and to utilize the exposure data ant icipated to be received from the post

- RED DCI

.


### 3.3.1 Occupational Handler Exposure EPA anticipates the need to revise the occupational handler assessment conducted in support of the 2008 RED. The ORE was conducted on March, 2008 ( D344853 ). Occupational handler d ermal and inhalation exposures to D I MTS were assessed in the RED for the following applications: liquid pour, liquid pump, solid pour, solid place , paintbrush/roller, pressure treatment, non

- pressure treatment (dip and spray) and airless sprayer . The agenc y expects to conduct new assessments for liquid pour

, solid pour , paintbrush/roller, pressure treatment and airless sprayer scenarios in registration review upon receipt of the anticipated exposure data expected from the RED DCI. These exposures were origi nally assessed using unit exposure data from the Pesticide Handler Exposure Database (PHED) and Chemical Manufacturer’s Association (CMA) data in the RED.

Table 10

– Occupational Handler Exposure Scenarios for D I MTS

Scenario Expos ure Route(s) Duration
Occupational Exposures
Open Pour of Liquids for Material Preservatives * Dermal Inhalation Short and Intermediate Term

Solid Pour of Wettable Powders for Material Preservatives * Dermal Inhalation Short and Intermediate Term
Application of Paints and Stains (Brush/Roller and Airless Sprayer) Dermal Inhalation Short and Intermediate Term

Sapstain Dip for Wood Preservatives Dermal Inhalation Short

, Intermediate and Long

- term
Sapstain Spray for Wood Preservatives Dermal Inhal ation Short

, Intermediate , and Long

- term

Pressure Treatment for Wood Preservatives Dermal Inhalation Short

, Intermediate and Long

- term * material preservatives will include uses such as paints, adhesives and caulks, slurries, emulsions, plastics and viny l products, leather tanning, and paper and paper board.



### 3.3.2 

### Occupational Post

- application Exposure Based on the low vapor pressure (~1E

- 6 mm Hg) of the active ingredient, EPA does not expect that DIMTS will volatilize in dry paint. Therefore, EPA will not con duct a post

- application inhalation assessment for treated paint. Workers can be exposed to DIMTS while working at wood pressure plants and non

- pressure treatment plants (sapstain dip and spray scenarios). The typical workers at pressure treatment facilitie s include tram setters, stacker operators, loader operators, QA/AC test borers, and tallymen. The typical workers at non

- pressure treatment facilities includes chemical operators, loader operator, graders, millwrights, trim saw operators, and clean

- up crew s. Although worker exposure at pressure and non

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Page 23 of 79 could be considered post

- application, EPA will include these exposures collectively as occupational handler scenarios in registration review and will conduct an updated assessment i n registration review for both the pressure treatment and non

- pressure treatment scenarios upon receipt of the required data from the RED DCI.


### 3.3.3 Residential Handler Exposures

EPA anticipates the need to revise the residential handler assessment conducted in support of the 200 8 RED. Residential handler dermal and inhalation exposures to D I MTS were assessed in the RED for paint brush/roller and airless spray application of paints and stains and finger painting (dermal). The quantitative exposure/risk assessmen t to be developed for residential handlers will be based on the following scenarios presented in Table 11

.
Table 11

– Residential Handler Exposure Scenarios for D I MTS

Scenario Exposure Route(s) Duration Residential Exposures Applications of paints and stains from brush/roller Dermal Inhalation Short Term

Applying of paints and stains from airless sprayer Dermal Inhalation Short Term



### 3.3.4 Residential Post

- Application Exposures

EPA anticipates the need to revise the resident ial post

- application assessment conducted in support of the 200 8 RED. Residential post

- application exposures result when adults and children come in contact with diiodomethyl p

- tolyl sulfone in areas where pesticide end

- use products have recently been appl ied (e.g., treated wood), or when children incidentally ingest the pesticide residues through mouthing the treated end

- products/treated articles (i.e., hand

- to

- mouth of finger paints). The quantitative exposure/risk assessment to be developed for residenti al post

application exposure will be based on the following scenarios presented in Table 12 . The a gency required post

- application data (indoor surface residue data, product use and description of product use) during the RED data call

- in to support these us es. A residential post

- application assessment for textiles and plastics will not be conducted because textile use is restricted to non

clothing use only and to carpet backing and plastics not to be manufactured into toys.

Table 12

– Residential Post

- Application Exposure Scenarios for D I MTS

Scenario Exposure Route(s) Duration Residential Exposures
Post application exposure to toddlers from finger paints with preserved inks. Dermal Incidental oral Short Term Post application exposure to toddlers from pressure treated wood used on decks and play sets Dermal Incidental oral Short TermDocket Number EPA

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## 3.4 Aggregate and Cumulative Exposure

3.4.1 Aggregate Exposures

E PA anticipates the need to revise the aggregate assessment conducted in support of the 2005 RED. Upon a reevaluation and selection of toxicological endpoints, combined with the human health exposure assessments expected as a part of this registration review case, aggregate exposures will likely need to be assessed. This assessment is anticip ated to include indirect chronic dietary ( food and drinking water ) ( e.g ., adhesives , paper/paper products and polymers ) exposures and residential exposures ( e.g ., residential handler in paint and post

- application exposures for wood treatment).



### 3.4.2 Cumulative E xposures
With respect to cumulative exposure, unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to DIMTS and any other substanc es , and DIMTS does not appear to produce a toxic metabolite produced by other substances. For the purposes of this registration review, therefore, EPA has not assumed that DIMTS has a common mechanism of toxicity with other substances. For information rega rding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see http://www.epa.gov/pesticides/cumulative/

. 

## 4 Environm ental Risk Assessment

The agency anticipates the need to conduct an environmental risk assessment for DIMTS during registration review . Additionally, the agency anticipates the need to require additional ecological toxicity data for the registration revie w of DIMTS, based on the currently registered uses. There

was an ecological hazard and environmental risk assessment conducted on November 1, 2007 in support of the RED

. 1

The agency has not previously conducted a risk assessment that supports a complete endangered species determination for DIMTS. The ecological risk assessment planned during registration review will allow the agency to determine potential acute and chronic risks to aquatic organisms exposed to DIMTS and its degradates that are transport ed from treatment sites into the aquatic environment. Such sites include antisapstain uses, leather tanning, paint preservation, adhesives, caulks, and sealants, rubber and plastics, paper production, and paper preservation during storage

. All uses are a ssumed to have the potential to result in Down

- the

- Drain (DtD) exposure. In addition, the wood preservation and paper production use and the paint preservation use have the potential to result in runoff into the aquatic environment. Sorption and bioconce ntration of all residues are expected to be limited. The risk assessment will also allow the agency to determine whether each use of the DIMTS has 'no effect' or 'may affect' federally listed threatened or endangered species (listed species) or their desig nated critical habitats. When an assessment concludes that a pesticide’s use 'may affect' a listed species or its designated critical

1 Mostaghimi and Erickson.Docket Number EPA

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Page 25 of 79 habitat, the agency will consult with the U.S. Fish and Wildlife Service and/or National Marine Fisheries Services (the Se rvices), as appropriate.



## 4.1 Environmental Fate Assessment

T h e environmental fate assessment will address the persistence and mobility of parent DIMTS and the degradates MIM P TS, MPTS , and PTSOA

.
DIMTS is stable to hydrolysis at pH 5, but degrades with half

- l ives of 2.1 days at pH 7 and 3.4 days at pH 9 (MRID 43008701) . It degraded rapidly in irradiated water with a half

- life of 1.4 hour (MRID 47343001)) ; h owever, photodegradation is expected to be limited because of the lack of light penetration caused by su spended sediment and shading. Photodegradation on soil occurred with a half

- life of 5.3 days (MRID 47323601). In soil, DIMTS is rapidly degraded with half

- lives of 1.5 day under aerobic conditions (MRID 41765405) and 4.2 days under anaerobic conditions ( MRID 41765406). Under anaerobic aquatic conditions representing bottom sediment, DIMTS degraded with a half

- life of 9.6 days and residues are expected to partition to water rather than sediment (MRID 42177201). Data on parent DIMTS have not been submitte d for leaching

- adsorption

- desorption and are anticipated to be required.

In the environment, DIMTS is relatively insoluble ( <2 mg/l, Table 4), but will largely partition to water in the presence of sediment based on the results of the environmental fate data in Appendix B. Even with its relatively low water solubility, DIMTS is not likely to bioconcentrate in aquatic organisms based on its log P value of 2.66 (<3, Table 4). Based on its low vapor pressure and Henry’s law constant (Table 4), it is unlike ly to move from soil or water into air. Although the water solubility of parent DIMTS is lower than for the degradates (Table 5), the environmental behavior of the degradates is expected to be similar to parent compound.

The degradates of DIMTS do not com pletely mineralize in the environment. MIMPTS was a terminal degradate (~10 % of applied parent) for photodegradation in water, but degraded with half

- lives of 12.5 days in irradiated soil, 32 days in aerobic soil, 21 days in anaerobic soil, and 11 days i n the anaerobic aquatic metabolism studies. MPTS was a minor degradate in the hydrolysis study, did not degrade in the photodegradation in water or the anaerobic soil and anaerobic aquatic metabolism studies, and was relatively persistent in aerobic soil with a half

- life of 53 days. PTSOA was the main terminal degradate (~90 % of applied parent) in the photodegradation in water study and was a minor degradate in the hydrolysis study. Acceptable data on leaching

- adsorption

- desorption in soils and sediment have not been submitted for MIMPTS and MPTS and are anticipated to be required. Leaching

- adsorption

- desorption data on PTSOA are not anticipated to be required because the only study with significant quantities of PTSOA formed was photodegradation in wat er, and this route of dissipation is expected to be limited because of suspended sediment and shading.

Based on a wood leaching stud y using submerged blocks (MRID 47375907), DIMTS leached from treated wood (5.6 mg/cm 3 ) with maximum, minimum, and average ra tes of 23.5, 19.1, and 20.4 μg/cm 2 /day and cumulative rates of 309 μg/cm 2

. The leached portion of DIMTS was 17.9 % (Table B1). The leaching rate was relatively constant in the study. These leaching rates are the most relevant because the treatment rate in the study (1 % w/w) was the closest to 0.12

- 0.32 % w/w rate in Label Reg. No. 464

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### 4.1.1 W aste Water Treatment Plants (W WTP )

DIMTS was readily biodegradable in WWTP simulations studies at 0.05 and 0.5 mg/L (MRID 47024601) but was not readily biodegradab le at 28

- 67 mg/L (MRID 47338401 ). Even though DIMTS was readily biodegradable in MRID 47024601, DIMTS was only primarily biodegradable but not ultimately biodegradable at 0.05 and 0.5 mg/L because the test material primarily formed terminal degradates oth er than CO 2 and water. T he half

- lives of the degradate MIMPTS were 1.2 day at 0.05 mg/L and 12.6 days at 0.5 mg/L. The degradate MPTS did not degrade in MRID 47024601. In a modified Zahn

- Wellens test (OECD 302B)

, the degradate MPTS was studied as a pare nt compound, and was not ultimately biodegradable because only about 48 % (<70 %) of dissolved organic carbon (DOC) was removed in 28 days (MRID 47375909). In an ASRI study (MRID 47373803), DIMTS was not toxic to WWTP organisms when tested at up to >4.5 t imes the water solubility (<2 mg/L, Table 4). Because DIMTS is not expected to reach concentrations as high as 9 mg/L based on its solubility of <2 mg/L, no further ASRI testing is needed for DIMTS or its degradates.



### 4.1.2 Water Quality

DIMTS and its degradate s are not identified as a cause of impairment for any water bodies listed as impaired under section 303(d) of the Clean Water Act

. 2 In addition, no Total Maximum Daily Loads (TMDL) have been developed for DIMTS and its degr a dates

. 3 More information

on impaired water bodies and TMDLs can be found at EPA’s website

. 4



## 4.2 Conceptual Model s for Environmental Exposure Pathways

Based on the registered use of DIMTS as well as physical/chemical properties and environmental fate data for DIMTS and its degradates

, the a gency cannot rule out the possibility that aquatic organisms downstream of wastewater treatment facilities that receive discharges have the potential to be exposed to DIMTS and/or its degradates. The a gency has created conceptual models for potential routes of environmental exposure which are included in “Conceptual Models for Environmental Exposure Pathways of Antimicrobial Pesticides ”

, found in the docket
at www.regulations.gov , EPA

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- 0638

- 0002. A conceptual model of pulp and paper mill systems can be found on page 26, and for the antisapstain use, may be seen on p. 29. Conceptual models for textiles (including rubber, plastics, and leather) may be seen on pp. 15

- 16, and for adhesives, caulks, and sealants, may be seen on p. 17. Based on the summary of registered uses of DIMTS presented in Table 6 , the chemical/physical properties of parent DIMTS in Table 4 and the degradates in Table 5 , and the e nvironmental fate data presented in Appendix B, the agency has developed conceptual model diagrams for exposure of ecological organisms to DIMTS and its major degradates

. In the environmental fate studies, DIMTS forms MIM P TS and MPT S degradates, which are more persistent and water soluble than the parent compound. The PTSOA degradate , while also

2 http://iaspub.epa.gov/tmdl_waters10/attains_nation_cy.cause_detail_303d?p_cause_group_id=885
3 http://iaspub.epa.gov/tmdl_waters10/attains_nation.tmdl_pollutant_detail?p_pollutant_group_id=885&p_pollutant_ group_name=PESTICIDES

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Page 27 of 79 formed, was only detected at significant concentrations in the photodegradation in water study, and this route of dissipation is expected to be limited because of suspended sediment and shading in surface water. Therefore, PTSOA is not expected to be included in the planned risk
assessment. MPTS is the terminal degradate under most environmental conditions and did not mineralize in a Zahn

- Wellens biodegradation simulation test (MRID 47375909 ). As a result, MPTS is expected to be present in the water phase of effluent with Down

- the

- Drain exposure and from treated paint used outdoors.

The screening

- level risk assessment that will be conducted as part of this registration review will evaluate potential risks to ec ological organisms from exposure to parent DIMTS and the degradates MIMPTS and MPTS.



## 4.3 Ecological Effects Assessment

4.3.1 Mechanism of Action

In diiodomethyl p

- tolyl sulfone , the bonds between the methyl carbon and both halogen substituents are highly polarized b y the electronegative iodide and sulfone groups, destabilizing the bonds and contributing to their partial ionic character

. The toxicity of the chemical results from the successive liberation of each halide substituen t. Free iodide may then react with nu cleic acids, fatty acids, and proteins.

In vertebrates

, iodine complexes with the amino acid tyrosine to form hormones with important roles in the regulation of homeostasis, growth and development, and metabolism. Some effects in vertebrates may result f rom the influence of excess iodine on the production of these hormones.



### 4.3.2 Measures of Effect (Ecotoxicology Endpoints)

Ecotoxicity endpoint data are used as measures of effects to aquatic and terrestrial organisms. All available ecotoxicity endpoints in the a gency ’s files f or DIMTS studies submitted by registrants or other interested parties, federal laboratory data, or from the public literature are tabulated in Appendix C along with the data requirements and dat a gaps. There are currently no ecotoxicity data for DIMTS degradates. The most sensitive values for each receptor group used for the previous risk assessment are seen in Table 13

. These selected endpoints will be updated during the risk assessment phase fo r registration review based on any additional submitted data or data found in the public literature.

Table 13

– Selected Ecological Effects Endpoints for Risk Assessment of DIMTS

Receptor

Group Surrogate Species Risk Scenario Tox icity Endpoint Reference (MRID)

Freshwater fish Rainbow trout Acute 96

- h LC 50 = 66.7 ug/L 47234001
Rainbow trout Chronic Data Gap

-- Freshwater invertebrates Daphnia magna Acute 48

- h EC 50 = 279 ug/L 47234002 Chronic Data Gap

--
Estuarine/marine fis h Sheepshead minnow Acute Data Gap

-- Chronic Not required A

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Page 28 of 79 Receptor

Group Surrogate Species Risk Scenario Tox icity Endpoint Reference (MRID)

Estuarine/marine

invertebrates Eastern oyster Acute Data Gap

--
Mysid Shrimp Acute Data Gap

-- Chronic Not required A

-- Algae Green alga Non

- listed Data Gap

--

Blue

- Green Algae Cyano bacteria Non

- listed Data Gap

-- Aquatic vascular plants Duckweed Non

- listed Data Gap

--

Seedling Emergence Rice Non

- listed Not required B

--

Vegetative vigor Rice Non

- listed Not required B

--

Birds Northern bobwhite quail Acute LD 50 = >2000 mg/kg 123643

Mallard duck Subacute dietary LC 50 = >5620 mg/kg 1 24488

Chronic Not required A

--

Mammals See Table 9 C Acute LD 50 = >5000 mg/kg (males) LD 50 = >5000 mg/kg (females) 41765401,43608702, 42586801 Chronic NOAEL = 10 mg/kg/day 46913 301
Nontarget insects Honey bee Acute Data Gap

--

A Not required for this use pattern.

B Not required. No significant exposure anticipated.
C Test species used in Human Health Risk Assessment will be used as surrogates for mammalian ecotoxicity

assessm ent.


## 4.4 Exposure Analysis Plan

4.4.1 Aquatic and Terrestrial Wildlife Exposure Estimates

Available models will be used to determine the estimated environmental concentration (EECs) in the aquatic environment. Resulting exposure estimates will be compared to the t oxicity endpoints to determine if levels of concern are exceeded for each receptor group.



### 4.4.2 Screening Level Down

- the

- Drain Analysis

The Down

- the

- Drain (DtD) module of E

- FAST (Exposure and Fate Assessment Screening Tool) was used to determine the potential f or aquatic organisms downstream of domestic wastewater treatment plants that receive discharges from end

- use of DIMTS to be exposed to DIMTS and its degradates. The results of the DtD module runs are expressed as number of days of exceedance of concentrat ions of concern (COC) for aquatic organisms. A detailed description of derivation of data for input parameters selected to run the DtD module and of the theoretical basis for this model is presented in Appendix E. A conservative assumption of no removal during wastewater treatment was used in DtD model runs.Docket Number EPA

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Page 29 of 79 The DtD analysis for DIMTS is intended to serve two purposes: (1) to demonstrate the maximum WWTP influent volume of DIMTS that would trigger potential concerns for aquatic organisms exposed to DIMTS or its degradates downstream of domestic wastewater treatment plants and (2) to evaluate potential exposures based on the assumptions that the total production volume of DIMTS enters domestic wastewater treatment plants. A key purpose of the DtD analysis for DIMTS is to determine the lowest maximum annual WWTP influent volumes of DIMTS that would trigger potential concerns for aquatic organisms downstream of domestic WWTPs.

Table 14 presents results of a screening

- level DtD analysis for DIMTS which is bas ed on laboratory toxicity data for freshwater organisms. Based on these aquatic toxicity data and the estimated pro duction volume which is expected to be no greater than 250,000 kilograms per year, t he DtD model predicted 89 days per year exceed a nces of c oncentrations of concern for endangered freshwater fish ( a cute). However, using the average case scenarios, the exceedanc e for endangered fresh water fish (acute) was less than 10 days per year.

Table 14

– Summary of Screening L evel Down

- the

- Drain Analysis Results for Aquatic Organisms

High End Scenario

WWTP Influent Volume Freshwater Fish Acute (COC = 33.35 ug/L) Endangered Freshwater Fish Acute (COC = 3.33 ug/L)

250

, 000 kilograms/year Exceeded 2 day s per year Exceeded 89 day s per year

WWTP Influent Volume Freshwater Invertebrates Acute (COC = 139.5 ug/L) Endangered Freshwater Invertebrates Acute (COC = 13.95 ug/L)

250

, 000 kilograms/year No e xceedance Exc eeded 13 day s per year

Average

– Case Scenario

WWTP Influent Volume Freshwater Fish Acute (COC = 33.35 ug/L) Endangered Freshwater Fish Acute (COC = 3.33 ug/L)

250

, 000 kilograms/year Exceeded less than a day
per year Exceeded 10 day s per year

WWTP Influent Volume Freshwater Invertebrates Acute (COC = 139.5 ug/L) Endangered Freshwater Invertebrates Acute (COC = 13.95 ug/L)

250

, 000 kilograms/year No exceedance Exceeded 1 day per year

This screening level analysis assumes that DIMTS and degradates are released to domestic wastewater treatment plants. Based on registered uses of DIMTS and degradates presented in Table 6 of this PWP, there are some uses, such as paper production, for w hich discharges may enter industrial WWTPs rather than domestic WWTPs prior to entering surface water. DifferentDocket Number EPA

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Page 30 of 79 methods and tools for assessing potential exposures and associated ecological risks will be applied for these other types of uses.



## 4.5 Effects Anal ysis Plan

Additional open literature studies will be identified through EPA’s ECOTOXicology (ECOTOX) database. The ECOTOX database will be searched during the risk assessment phase of DIMTS and the data reviewed following the agency’s policy for reviewing public literature for use in assessing risks from pesticide s

. Those ecotoxicity values found in the public literature to be more sensitive than those currently in Table 13 and or which satisfy an existing data gap(s) will be used during the risk assessmen t phase of DIMTS to update Table 13

. ECOTOX was created and is maintained by the USEPA, Office of Research and Development, and the National Health and Environmental Effects Research Laboratory's (NHERL) Mid

- Continent Ecology Division.


## 5 Endocrine Disruptor Screening Program (EDSP)

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carc inogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cy clicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of its reregistration decision for DIMTS , EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), D IMTS is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wild life similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two

- tiered approach to making the statutorily required determinations. Tier 1 consists of a batte ry of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E , A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine

- related effects caused by the substance, and establish a dose

- response relationship between the dose and the E, A, or T effect.

Under FFDCA section 408(p), the agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second list of chemicalsDocket Number EPA

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Page 31 of 79 identified for EDSP screening was published on June 14, 2013 5 and includes some pesticides scheduled for registratio n review and chemicals found in water

. Neither of these lists should be construed as a list of known or likely endocrine disruptors.

For further information on the status of the EDSP, the policies and procedures, the lists of chemicals, future lists, the t est guidelines and the Tier 1 screening battery, please visit our website

. 6


## 6 Optional Label Changes

The agency invites comment on any label amendments that could be considered to eliminate the anticipa ted need for EPA to require certain data, reduce the po ssibility that EPA’s planned risk assessments overestimate risk due to reliance on conservative assumptions, and/or improve label clarity

. A dditionally, a s discussed in Section 3.2.1., i f the registered DIMTS labels intend to treat paper that may contact f ood, the labels should be revised to comply with the FDA food additive regulation level of 0.2 lb a.i. per ton of dry weight fiber.


## 7 Guidance for Commenters

7.1 Preliminary Work Plan
The public is invited to comment on EPA’s Preliminary Work Plan and rationa le. The agency will carefully consider all comments as well as any additional information or data provided in a timely manner prior to issuing a final work plan for the DIMTS registration review case.



### 7.1.1 Trade Irritants Through the registration review proces s, the agency intends to solicit information on trade irritants and, to the extent feasible, take steps toward facilitating irritant resolution. The a gency will work to harmonize tolerances and international maximum residue limits (MRLs) and may modify tol erance levels to do so, when possible. Stakeholders are asked to comment on any trade irritant issues resulting from lack of MRLs or disparities between U.S. tolerances and MRLs in key export markets, providing as much specificity as possible regarding the nature of the concern.



### 7.1.2 Water Quality

The agency invites submission of water quality data for this pesticide. To the extent possible, data should conform to the quality standards in Appendix A of the OPP Standard Operating Procedure: Inclusion of Impaired Water Body and Other Water Quality Data in OPP’s Registration Review Risk Assessment and Management Process 7 in order to ensure they can be used quantitatively or qualitatively in pesticide risk assessments.

5 See http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPPT

- 2009

- 0477

- 0074 for the final second list of

chemicals.

6 http://www.epa.gov/endo/.

7 http://www.epa.gov/oppsrrd1/registration_review/water_quality_sop.htm

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Page 32 of 79 

### 7.1.3 Environmental Justice

EPA seeks to achieve envi ronmental justice, the fair treatment and meaningful involvement of all people, regardless of race, color, national origin, or income, in the development, implementation, and enforcement of environmental laws, regulations, and policies. To help address pot ential environmental justice issues, the agency seeks information on any groups or segments of the population who, as a result of their location, cultural practices, or other factors, may have atypical, unusually high exposure to DIMTS compared to the gene ral population. Please comment if you are aware of any sub

- populations that may have atypical, unusually high exposure compared to the general population.



### 7.1.4 Structure Activity Relationships EPA must rely upon information of appropriate quality and reliabili ty for each decision made by the agency . In the OPP, the evaluation process for a pesticide chemical traditionally begins with the applicant’s submission of a set of studies conducted with the specific pesticide chemical of interest. The use of the results of such testing (measured data) is a logical, scientifically rigorous process that identifies the physical, chemical, and environmental fate properties of the pesticide, as well as the dose and endpoints at which an adverse effect can occur in various ani mal species.

Today, there is significant interest in alternative techniques, i.e., techniques other than data generation that could significantly inform the agency ’s decision

- making process. Recently, OPP has made increasing use of structure activity rela tionship (SAR) as part of its regulatory decision

- making process. In the SAR process, a chemical's molecular structure is compared to that of other chemicals for which data are available. These structural similarities are then used to make predictive judgm ents about a chemical’s physical, chemical, and biological properties. Thus, the chemical’s physical, chemical, and biological properties are a function of (or directly related to) the chemical’s molecular structure. Quantitative SAR is referred to as QSAR . To develop a QSAR, a selected set of measured data on a single physical, chemical, or biological property is used to derive a model (an equation) to predict the value of that property.

Since SAR assessments and QSAR modeling are another set of tools tha t are available to agency scientists, OPP has begun a process shift that envisions shifting from the current study

- by

- study approach to an approach in which the use of predicted data, generated using validated models, is considered along with information f rom open literature and studies specifically generated under Part 161 requirements. All relevant information would be considered as part of a weight

- of

- the

evidence evaluation.

At this time, EPA believes that for certain endpoints, especially physical/che mical and fate properties, that SAR and QSAR might be effectively utilized to fulfill these data requirements for many antimicrobial pesticide chemicals. When considering biological properties, at this time, EPA believes that SAR and QSAR can be most effec tively utilized in the evaluation of chemicals that exhibit lower toxicity for human health and/or ecotoxicity parameters. This is appropriate because the risk assessment for lower toxicity chemicals can be stream

- lined, i.e., a screening

- level assessment procedure rather than multiple tiers of assessments with progressively more data requirements.Docket Number EPA

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Page 33 of 79 If stakeholders believe that submission of predicted data can fulfill one of the data needs for the DIMTS ca se, then the agency invites submission of this infor mation. The submitter would be expected to supply a rationale describing the utility of the information and provide documentation on the scientific validity of the information. The determination that the predicted data fulfills the data requirement would b e at the sole discretion of the agency . Pre

- submission consultation with the agency is encouraged.



### 7.1.5 Additional Information

Stakeholders are also specifically asked to provide available information and data that will assist the agency in refining its risk assessments, including any species

- specific ecological effects determinations. The agency is interested in receiving the following information:

1. Confirmation on the following label information: A. Sites of application B. Formulations C. Application methods and e quipment D. Maximum application rates E. Frequency of application, application intervals and maximum number of applications F. Geographic limitations on use 2. Use or potential use distribution 3. Use history 4. Usage/use information for non

- agricultural uses (e.g., m aterials preservation) 5. Typical application interval 6. State or local use restrictions 7. Ecological incidents (non

- target plant damage and avian, fish, reptilian, amphibian and mammalian mortalities) not already reported to the agency 8. Monitoring data


## 8 Next Steps

After the 60

- day comment period closes in November 2015 , the agency will review and respond to any comments received and then issue a Final Work Plan for the DIMTS case.Docket Number EPA

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Page 34 of 79 

## 9 References

Chemical Book. 2010. METHYL P

- TOLYL SULFONE

. http://www.chemicalbook.com/ChemicalProductProperty_EN_CB8463935.htm

. Dow MSDS. August 11, 2011. Material Safety Data Sheet: DIMTS

. http://msdssearch.dow.com/publishedliteraturedowcom/dh_0819/0901b80380819eaa.pdf?filepat h =.

EPI

- WEB 4.11. 2012. http://www.epa.gov/opp t/exposure/pubs/episuitedl.htm

. Mostaghimi, Siroos. November 1, 2 007. Antisapstain Modeling for AMICAL ((Benzene, 1

- ((diiodomethyl)sulfonyl)

- 4

- methyl) . No DP Barcode.

MRID 42177202

. Laster, W.; McGowan, N. (1991) Octanol/ Water Partition Coefficient of DIMTS : Final Report: Lab Project Number: 39209. Unpublished study prepared by ABC Labs, Inc. 377 p.

MRID 47234003. Lopez, A. (2007) Determination of UV/Visible Absorption Characteristics of DIMTS Antifungal Agent. Project Number: 1654W. Unpublished st udy prepared by PTRL West, Inc. 29 p.

MRID 47373801

. Sinning, D. (2003) Physical and Chemical Characteristics of DIMTS : Melting Point, Boiling Point, Density, Water Solubility, and Vapor Pressure. Project Number: 2310/16, 020030. Unpublished study prepare d by Case Consulting Laboratories, Inc. 12 p.

MRID 47338402

. Hunziker, R.W. (2007) Estimation of Water Solubility Limit, Octanol

- Water Partitioning Constant, and Aquatic Toxicity of Monoiodo

- p

- methyltolysulphone and p

Methyltolylsulphone Which Are Breakdo wn Products of the Biocidal Active di

- iodo

- methyl

para

- tolyl

- sulphon (DIMTS). Project Number: DR/0122/8542/003. Unpublished study prepared by Dow Chemical Europe and Dow Chemical Co. 16 p.

MRID 47373801

. Sinning, D. (2003) Physical and Chemical Character istics of DIMTS : Melting Point, Boiling Point, Density, Water Solubility, and Vapor Pressure. Project Number: 2310/16, 020030. Unpublished study prepared by Case Consulting Laboratories, Inc. 12 p.

MRID 48511201

. O'Connor, B.; Woolley, S. (2011) DIMTS : D etermination of Dissociation Constants in Water. Project Number: 41005025, 24P/2010/030, GLP/2011/024. Unpublished study prepared by Harlan Laboratories, Ltd. 13 p.

U.S. Environmental Protection Agency (EPA). 2002. ECOTOX User Guide: ECOTOXicology Databa se System. Version 3.0. Available: http://www.epa.gov/ecotox/

.

U.S. Environmental Protection Agency . High Production Volume Information System (HPVIS). http://www.epa.gov/hpvis/

.Docket Number EPA

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Page 35 of 79 

# Appendix A T oxicology Profile

Acute Toxici ty for Product Labeling

As listed in Table A1, diiodomethyl p

- tolyl sulfone was found to be minimally toxic for acute oral and dermal toxicity (Toxicity Category IV for both) and low toxic for inhalation toxicity (Toxicity Category III). It caused severe irritation to the ocular tissue of rabbits (Category I) but minimal irritation to the skin of rabbits (Category IV)

. Diiodomethyl p

- tolyl sulfone is a dermal sensitizer.

Table A1

– Acute Toxicity Studies for Diiodomethyl p

- tolyl S ulfone

Guideline No./ Stu dy Type MRID No. Results Toxicity Category 870.1100/ Acute oral toxicity 41765401 / 43008702 LD50 > 5 000 mg/kg for both males and females I V

870.1200/ Acute dermal toxicity 00123023 LD50 ( male rats ) > 20000 mg/kg I V

870.1300/ Acute inhalation toxici ty 43660901 & 00087842 LC 50 (combined)= 0.96 mg/L LC 50 (male) = 1.15 mg/L LC 50 (female) = 0.77 mg/L III

870.2400/ Acute eye irritation 41765402 / 43008703 Severe irritant (r abbit ) I

870.2500/ Acute dermal irritation 41765403/43008704 Minimum irritant (rabbit) I V

870.2600/ Skin sensitization 48293901 A d ermal s ensitizer



## Subchronic Toxicity

Adequacy of Database for Subchronic Toxicity: The database for subchronic toxicity is considered adequate

. There are several studies in the agency’s hazard dat abase to address subchronic oral toxicity , including two 90

- day oral (diet) toxicity stud ies in rats (MRID s 42054402/43246401 and 47338201 ) , a 90

- day oral (capsule) toxicity study in dogs (MRID 42054403/43246402), a 28

- day dermal study in rats (MRID 482369 01), and a 90

- day inhalation toxicity stud y (MRID 48 2 64901 ). A brief summary of each of the studies is provided below.

870.3100 90

- Day (13

- Week) Oral Toxicity

– Rat

(1) In a subchronic oral toxicity study ( MRID 42054402/43246401 ), groups of Crl:CD(SD)BR

r ats (10/sex/group) received the test material d iiodomethyl p

- tolyl sulfone (≥ 95% a.i.; Lot #68

- 332

- CB ) at concentration s of 0, 5

, 2 0, or 8 0 (15/sex) mg/kg/day, in the diet, for 90

- 94 day s

.

No s ignificant diff erence in body weight and mean weight gains wer e noted among treatment group s

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Page 36 of 79 elevations in mean phos phorus and cholesterol l e vels in th e high dos e group males and squamous metaplasia of the s a livary gland ducts in thr ee mal es in the high dos e group. All of the effects noticed in the treatment groups were not considered toxicologically significant. The highest dose does not reach the maximum tolerated dose (MTD). The study is classified as Core

- Minimum and can be consid ered for hazard assessment.

(2) In a subchronic oral toxicity study (MRID 47338201), groups of Sprague

- Dawley (CD) rats (8/sex/group) received the test material diiodomethyl p

- tolyl sulfone (97.4±0.01% a.i.; Lot # PB1631LA01) at concentrations of 0, 5, 20 , 100, or 250 mg/kg/day, in the diet, for at least 13 weeks. Data generated in this study were used to establish the doses for a subsequent two

generation reproduction study.

There were no treatment

- related deaths or signs of clinic toxicity. Feed consum ption was significantly decreased during the first half of the study in males in the two high

- dose groups and in females in the highest dose group, accompanied with a lower termination body weight (approximately 10% relative to the controls) in both the hi ghest dose males and females.

Slightly higher liver and salivary glands weights were noted in rats in the highest dose group compared to the controls, with the relative weights of these organs statistically identified. Histopathological alterations wer e noted in the stomach, liver, and salivary glands of the highest dose animals, including hyperplasia of the non

- glandular mucosa in all highest dose (250 mg/kg/day) animals with erosions, ulcers or inflammatory changes, generalized slight hypertrophy of t he hepatocytes, and squamous metaplasia of the salivary gland ducts, primarily the intra

- lobular duct of the submandibular gland. Some rats given 100 mg/kg/day also exhibited hyperplasia of the non

- glandular mucosa of the stomach and squamous metaplasia of the salivary glands. “Based on these data, the no

- observed

- adverse effect level (NOAEL) was considered to be 20 mg/kg/day.” A final conclusion will be provid ed after the a gency’s comprehensive review of the study.

870.31 5 0 90

- Day (13

- Week) Oral Toxicity

– Dog In a subchronic oral toxicity study (MRID 42054403/43246402 ), groups of beagle dogs (4/sex/group) were administered the test material d iiodomethyl p

- tolyl sulfone ((≥ 95% a.i.; Lot # 68

- 332

- CB ) at doses of 0, 2

, 10 , or 6 0 mg/kg/day, in gelatin ca psules, for 96

- 100 days.

C linical signs of toxicity , which were observed 1

- 4 hours after do sing in the high dos age group, includ e d decreases activity, d e hydration, mu coid e ye di scharge

, weakene d condition and abnormal fec es (mucoid and occa sionally blood

- ting ed). Eye discharge and abnormal f eces in th e intermediate do sage group w ere also considered treatment related

. Females in the high dosage group had at least 20 % decrea ses in mean body weight gain, in

c omparison to the control value , from d ay 0 to 91

.
Mean he m atology e valuation s of the treate d animal s w ere not s tat is tically significant from tho se of the control animal s , although the white blood cell count and ne utrophil count s of th e male s in the 60 mg /kg/day group w ere highe r than the control and oth er treated groups. The high dosage group males also had significantly decreased mean calcium, albumin, albumin:globulin ratio, and total protein values on one of two evaluat ions during the treatment period.Docket Number EPA

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Page 37 of 79 On gross necropsy, the only findings were changes in the gastrointestinal tract (patchy

- red discoloration of the stomach and mucoid appearance of the small intestines) in three males in the high dosage group. Absolute and relative organ weight did not differ from the control values.

On histopathology, degeneration of the thyroid gland (mineralization within colloid clumping of sloughed follicular cells and colloid depletion) was observed in males and females in the high

a nd intermediate dosage groups. Sialadenitis (ductal and periductal inflammation of the salivary gland), hemorrhagic gastritis, necrosis of the small intestine and keratitis were also observed in the high dose group.

The no

- observed

- adverse

- effect

- level ( N OAEL ) was determined to be 2 mg/kg/day , based on histopathological changes observed in the thyroid glands, salivary gland and gastrointestinal (GI)
tract.
The study is classified as Core

- Minimum and can be considered for hazard assessment.

870.3200 Subch ronic (21 /28

- day dermal) Toxicity

(1) In a subchronic dermal study ( MRID 48236901 ), d iiodomethyl p

- tolyl sulfone (purity 97.7%, Lot # PB1631LA01) was applied to a semi

- occluded skin of 10 Crl:CD(SD) rats /sex/dose at dose levels of 0, 20

, 100

, or 500 mg/kg bw/day, 6 hours/day

, 7 days/week , for 28 consecutive day s

. The animals were acclimated to dermal wraps for three days prior to dosing. T he fur of each test animal was clipped from the dorsal area of the trunk over an area of at least 10% of the body

sur face , starting at the scapulae (shoulders) to the wing of the ilium (hipbone) and half way down to the flank on each side of each animal.

There were no compound

- related effects in body weights, body weight gains or feed consumption in dosed male and female animals as compared to the controls.

Systemic effects related to the treatment included increased absolute and relative thyroid weights in high

- dose males. Thyroid histopathologic changes were observed in all treated males and females in the mid

- and hi gh

- dose groups. The thyroid effects included very slight hypertrophy of thyroid follicular epithelial cells and altered tinctorial properties of the colloid, characterized by the presence of pale to very pale eosinophilic colloid in the follicles of treat ed male and female animals as compared to the bright eosinophilic and homogeneous colloid in the controls.

Dermal reactions attributed to the test compound were observed in the high

- dose males including scratches, very slight edema, scabs of varying sever ities, and slight scaling. Similar dermal observations, as well as erythema, were reported in females in the mid

- and high

- dose groups. Necropsy and histopathological findings in the high

- dose males and the mid

- and high

- dose females, at the dermal appli cation site, were multifocal scabs, slight epidermal hyperplasia (acanthosis) with very slight parakeratosis, and very slight multifocal subacute to chronic inflammation in the dermis. The histopathology of the treatment

- related scabs at the dermal applic ation site consisted of multifocal epidermal ulceration, moderate epidermal hyperplasia, slight hyperkeratosis with parakeratosis, subcorneal pustules in the epidermis, and slight subacute to chronic multifocal inflammation of the dermis, which were attrib uted to scratching of the treated skin due to irritation of the test compound.Docket Number EPA

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Page 38 of 79 Additional changes considered to be secondary to the treatment

- related ulcerative dermal lesions were marginally higher serum aspartate aminotransferase activity in mid

- and hig h

- dose females, and very slight myeloid cell hyperplasia in the bone marrow, very slight splenic extr a medullary hematopoiesis , and increased white blood cell count with increased percentage of neutrophil cells in high

- dose females.

The NOAEL for systemi c toxicity is 20 mg/kg/day for females, based on thyroid effects but is not established for males

. The NOAEL for dermal effects is 20 mg/kg/day for both males and females.

This 28

- day dermal toxicity study in the rat is classified A cceptable /G uideline and satisfies the guideline requirement for a 28

- day dermal toxicity study (OPPTS 870.3200; OECD 410) in rats.

870.3 46 5 Subchronic (90

- day inhalation ) Toxicity

– Rat

In a subchronic inhalation study (MRID 48 2 64901 ), 1

- ((Diiodomethyl)su l fonyl)

- 4

- methyl

benzene (97.3% a.i.; Lot # PB1631LA01) was administered to 1 0 Crl:CD(SD) rats/sex / concentration by dynamic nose

- only exposure at analytic concentrations of 0, 1, 7, or 30 mg/m 3 for 6 hours / day, 5 days / week, for 13 weeks (65 total exposure days). The
average mass me dian aerodynamic diameter (MMAD) of the test material aerosol was 2.6

, 2.7

, and 2.6 μ m for exposure concentration groups 1, 7, and 30 mg / m 3 , respective l y.
Nine deaths occurred during the exposure phase of the study. These deaths includ e d: two control male s, one contro l female

, one mid

- concentration male, five high

- concentration males

, and one high

- concentration female. Study authors did not report whether deaths in the high concentration groups were considered treatment related. Gross patho l ogy observa t ion s were performed in only the high

- concentration group males and revealed mottled lungs and failure of lung deflation. No
treatment

- related changes regarding food consumption, in

- life b ody weights

, ophthalmology, clinical chemistry, or coagulation parameter s were observed. The mid

- and high

- concentration
group males and fema l es were observed with a slight, uni l ateral or bilateral parakeratosis with inflammation of the ventral meatus of the anterior nasal cavity. All affected males and females were also obser ved with irritation of the nasal septum. There were other treatment

- related effects in the nasolacrimal duct, larynx

, and trachea in males and females of the highes t concentration
group, including degeneration with or without inflammatio n , necrosis, and ne crotizing inflammation.

In addition, 4 of 10 high

- concentration males were observed with moderate to severe necrotizing bronchioalveolar inflammation of the lungs. Most high

- concentration group males and females exhibited inflammation of the alveolar sept a. Minor treatment

- related systemic effects were observed in the thyroid glands (colloid with altered tinctorial properties) of males and females exposed to mid to high concentrations of the test material.

High

- concentration group males had hemoglobin and hematocrit levels that were s tatistically significantly higher than controls. Although considered treatment related

, these l e vels were not interpreted to be toxicol o gically relevant by study authors. High

- concentration group female rats had a slight incre ase in neutrophils, and this increase was considered treatment re l ated. In addition, these female rats h ad an increase in alanine aminotransferase (ALT) and a non

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Page 39 of 79 statistically identified increase in aspartate aminotransferase (AST) without accompanying hi stopathological changes in the liver.

Terminal body weights for high

- concentration group males were decreased relative to controls, but although this difference was not statistically significant, study authors considered it related to
treatment. The high

- conce n tration group males were the only group to ha v e a statistically significant organ w e ight alteration, which was an increase in mean lung weight.

The LOAEC is 7 mg/m 3

, based on minor systemic effects in the thyroid glands and parakeratosis with inflam mation in the anterior nasal cavity in both male and female rats. The NOAEC is 1
mg / m 3

.

This subchronic inhalation toxicity study in the rat is classified A cceptable /G uideline and satisfies the guideline requirement for a subchronic inhalation study OPPTS 870.3465; OECD 413 in the rat.


## Developmental Toxicity

Adequacy of Database for Developmental Toxicity: The re are several studies in the agency’s hazard database to address developmental toxicity in both species, rats ( MRIDs 42054404/42054405/43246403 an d 47373805 ) and rabbits (MRIDs 42243801/ 43246404

, 47242202, and 47214601 )

. The available studies appear adequate, and a brief summary of each of the studies is provided below.

870.3700a Prenatal Developmental Toxicity (Gavage) Study

– Ra t

(1) In a developmental toxicity study (MRIDs 42054404/42054405/43246403), Crl:CD ® (SD)BR albino rats (22/group) received 0, 100, 300, or 1000 mg/kg/day d iiodomethyl p

- tolyl sulfone ( 95% a.i; Lot No. 66

- 207

- CB) by oral gavage from gestation days 6 thr ough 15 . Another developmental toxicity study (MRID 42054405) was conducted using the same strain of Crl:CD®(SD)BR albino rats (25/group) receiv ing the same test substance d iiodomethyl p

- tolyl sulfone ( 95% a.i; Lot No. 66

- 207

- CB) at 0 or 1000 mg/kg/day by oral gavage from gestation days 6 through 15

. Maternal toxicity was evident as reduced body weight gain and food consumption in the mid and high dose groups and as increased clinical signs of toxicity in the high dose group. The m aternal t oxicity LOAEL i s 300 mg/kg/day and the m aternal t oxicity NOAEL is 100 mg/kg/day , based on reduced body weight gain and food consumption.

Developmental toxicity was noted in the high dose group as slightly decreased mean litter size, increased number of resorptions relat ive to the number of implantation sites, reduced mean fetal body weight, increased incidences of umbilical hernia and incomplete ossification of the supraoccipital bones. The d evelopmental t oxicity LOAEL is 1000 mg/kg/day and the developmental t oxicity NOA EL is 300 mg/kg/day , based on decreased mean litter size, increased number of resorptions relative to the number of implantation sites, reduced meanDocket Number EPA

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Page 40 of 79 fetal body weight, increased incidences of umbilical hernia , and incomplete ossification of the supraoccipi tal bones.

The study is classified Core

- Guideline and satisfies the guideline requirement (OCSPP 870.3700), developmental toxicity (teratology) study in rats.

(2) In a developmental toxicity study in rats published by Ema et al ( MRID 47373805 [Ema et al, 1 992] ), pregnant Wistar rats (22/group) were administered diiodomethyl p

- tolyl sulfone (>95% a.i.) at doses of 0, 0.125, 0.25, 0.5 or 1.0% in the diet on gestational days 6

- 15. The estimated daily intakes of diiodomethyl p

- tolyl sulfone were 0, 100, 182, 28 8, or 411 mg/kg/day, respectively. Significant lower maternal body weight gain and food consumption were observed in the 0.25, 0.5 and 1.0% groups during the administration period. No significant changes induced by the test substance were detected in the n umbers of resorption, fetal death, or body weight of live fetuses. No evidence of teratogenesis was revealed in fetuses during morphological examination.

870.3700b Prenatal Developmental Toxicity (Gavage) Study

– Ra bbit

(1) In a deve lopmental toxicity study (MRIDs 42243801/ 43246404 ), pregnant New Zealand White rabbits received 0, 4, 15, or 60 mg/kg bw/day diiodomethyl

- p

- tolylsulfone (95% a.i.; Lot No. 66

- 207

- CB) by oral gavage from gestation day 6 through 18, inclusive.

Maternal toxic ity was noted as deaths and abortions primarily in the high dose group, clinical signs in the mid and high dose group, reduced body weight gain and food consumption in the mid and high dose groups. The m aternal t oxicity LOAEL is 15 mg/kg/day and the m atern al t oxicity NOAEL is 4 mg/kg/day, based on clinical signs (deaths) and decreas ed body weight gain and food consumption.

Developmental toxicity was noted in the mid and high dose in the form of decreased mean litter size, increased number of resorptions rel ative to the number of implantation sites as degenerating fetuses, and decreased postnatal survival and reduced mean fetal body weight in the mid dose (data only available for mid dose). At the mid dose, developmental effects also occurred in the form of i ncreased incidences of hydrocephalus (which was also noted at a low incidence in the rat developmental studies) and a slight increase in fetal and litter incidence of gnarled forepaw(s). An increase in incidence of unossified olecranon and sternebrae was n oted in the low

- and mid

- dose
groups. The d evelopmental t oxicity L OAEL is less than o r equal to (≤) 4 mg/kg/day, based on the increased fetal and litter incidence of unossified olecranon and unossified sternebrae. The d e velopmental t oxicity NOAEL was not e stablished (< 4 mg/kg/day)

. The study is classified Core

- Supplementary and does not satisfy the guideline requirement (OPPTS 870.3700) for developmental toxicity (teratology) study in rabbits, due to the lack of a NOAEL for developmental toxicity. In add ition, in the study, the fetuses were incubated at approximately 34°C for approximately 24 hours. A record of survival was kept over that period. Following incubation all fetuses in each litter were fixed in alcohol and examined for internal abnormalities. This is a procedure that is different from the current guideline requirement for a developmental toxicity (teratology) study in r abbits

. However, this study is considered anDocket Number EPA

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Page 41 of 79 acceptable study for maternal effects and can be used for risk assessment purpos es, despite its limitation in developmental effects.

( 2 ) In the developmental toxicity study (MRID 47242202 )

, diiodomethyl p

- tolyl sulfone ( 97.7% ± 0.1% a .i.; batch/lot PB1631LA01) was administered to 26 rabbits/dose by gavage at dose levels of 0, 0.05, 0. 5, or 2.0 mg/kg bw/day from days 7 through 27 of gestation.

Maternal toxicity was observed at 2 mg/kg/day, includ ing slightly increased absolute and relative thyroid weights . A n increased incidence of very slight thyroid follicular dilatation was also
not ed, which wa s consistent with iodine toxicity

, likely due to the high iodine content (60% by weight) of diiodomethyl p

- tolyl sulfone

. All the maternal effects are not toxicologically significant. The maternal NOAEL is 2 mg/kg bw/day.

No signs of developme ntal toxicity were observed at any dose level. The developmental NOAEL is 2.0 mg/kg bw/day , and the developmental LOAEL was not established

. The developmental toxicity study in the rabbit is classified Acceptable /Guideline and satisf ies the guideline requ irement for a developmental toxicity study (OPPTS 870.3700) in rabbits

. (3) In a range

- finding developmental toxicity study (MRID 47214601 )

, diiodomethyl p

- tolyl sulfone ( 97.7% ± 0.1% a .i.; batch/lot PB1631LA01) was administered to 7 New Zealand White rabb its/dose by gavage at dose levels of 0, 1

, 4

, 8, or 15 mg/kg bw/day from days 7 through 27 of gestation.

M aternal toxicity was evidenced

, at all tested dose levels , by increases in absolute and relative thyroid gland weights with corresponding thyroid fol licle dilatation (slight to moderate) and distension with colloid. N o appreciable follicular cell hyperplasia or hypertrophy was noted . One rabbit in each of the high

- dose groups ( 8 and 15 mg/kg/day ) aborted (GD 23, 24) following a period of decreased feed consumption, feces production, and body weight gain.

The re was higher incidence of post

- implantation loss in the two high

- dose groups of 8 and 15 mg/kg/day (26.4% and 20.6%, respectively vs. 4.6% in control ), which corresponded with increases in resorpti ons per litter and litters with resorptions, and decreases in litter size. There
were no treatment

- related developmental effects at 1 or 4 mg/kg/day. Both the maternal thyroid effects and the increases in post

- implantation loss are consistent with iodine t oxicity, most likely due to the iodine moieties of diiodomethyl p

- tolyl sulfone

. The a gency will reach a final conclusion after a comprehensive review of the study.


## Reproductive Toxicity

Adequacy of Database for Reproductive Toxicity: The database for rep roductive toxicity is considered adequate. There are two reproductive toxicity studies (one

- generation and two

generation) in rats in the a gency’s hazard database. A brief summary of each of the studies is provided below.

870.3800 Reproduction and Fertilit y EffectsDocket Number EPA

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Page 42 of 79 (1) In a n one

- generation reproductive toxicity study in rats (MRID 46913302), diiodomethyl p

tolyl sulfone (97.4%; Lot # PB1631LA01 ) was administered in the diet to 30 Sprague

- Dawley (Crl:CD [SD] IGS BR) rats/sex/dose group, at dietary levels of 0, 20, 80, or 200 mg/kg/day (adjusted time

- weighted average of 0/0, 21.8/20.7, 86.1/82.0, or 213.9/204.0 mg/kg/day in males/females, respectively), for approximately ten weeks prior to mating to produce the F1 litters. This study was originally designed as a two

- generation reproductive toxicity study, but was terminated during F1 littering due to high mortality in pups of the two highest treatment
groups.
Signs of toxicity occurred at all dose levels in the parental generation. Low

- do se females exhibited treatment

- related perinasal soiling

. T oxic effects observed in the mid

- dose group included the following: decreased food consumption and body weights in males and females; increased mortality in females; increased incidence of pale ski n/mucous membranes and perinasal soiling in females; decreased feces

, and palpebral closure in females. At the high

- dose level

, decreased food consumption and body weights in males and females was observed, as well as an increased mortality in females.

S e rum T3 (triiodothyronine) was decreased significantly (p≤0.05) by 26%, and TSH (thyroid stimulating hormone) was increased significantly (p≤0.05) by 98% compared to the surrogate controls. Grossly, diffuse roughened surface of the non

- glandular mucosa of t he stomach was observed, and additional treatment

- related, non

- specific findings of multifocal erosion/ulcer of the glandular mucosa of the stomach, decreased amount of fat, and decreased ingesta were noted. The following microscopic findings were also ob served: (i) very slight chromophobe hypertrophy of the pars distalis of the pituitary gland; (ii) very slight to slight multifocal metaplasia of the intralobular duct of the salivary gland; (iii) very slight to slight diffuse hyperplasia of the non

- glandul ar mucosa of the stomach; (iv) very slight altered tinctorial properties of the colloid of the thyroid gland; (v) very slight dilatation of the follicle of the thyroid gland; and (vi) very slight hypertrophy of the follicular cell of the thyroid gland.

Th e parental systemic NOAEL could not be established as all dose levels showed toxic effects. The parental systemic LOAEL is 20 mg/kg/day (adjusted time

- weighted average of 21.8/20.7 mg/kg/day in males/females)

, based on decreased body weights, body weight gains, and food consumption in the males and clinical signs of toxicity (red perinasal soiling that occurred around parturition in the females )

.

The offspring LOAEL is 20 mg/kg bw/day , based on decreased body weights at all levels. The offspring NOAEL co uld not be established

.
The reproductive LOAEL is 80 mg/kg bw/day in females , based on decreased gestation survival index. The reproductive NOAEL is 20 mg/kg bw/day in females

. There were no
treatment

- related toxic effects in males at any dose level, so a reproductive LOAEL for males cannot be calculated.

Many of the effects observed were due to iodine toxicity since diiodomethyl p

- tolyl sulfone is 60% iodine by weight. Consequently, a subsequent 2

- generation study was conducted, usingDocket Number EPA

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Page 43 of 79 more appropriate do se levels (MRID 46913301) . This study instead became the basis for dose selection in the two

- generation reproduction toxicity study.

This study is UNACCEPTABLE/GUIDELINE and does not satisfy the guideline requirement for a 2

- generation reproductive study (OPPTS 870.3800

, OECD 416 ) in rats due to the high mortality and iodine toxicity

. A subsequent 2

- generation study was conducted, usi ng more appropriate dose levels; therefore, this study can be used as a dose

- range finding study.

(2 ) In a two

- generation reproductive toxicity study in rats (MRID 46913301), diiodomethyl p

tolyl sulfone (97.4% a.i. ; Lot # PB1631LA01 ) was administered to 30 Sprague Dawley rats/sex/group at dietary levels of 0, 2.5, 10, or 40 mg a.i. /kg/day for two succ essive generations. The P generation animals were fed the test diets for approximately 10 weeks prior to mating to produce the F1 litters. All litters were weaned on PND 21, and one F1 weanling/sex/litter was randomly selected to be a parent of the next g eneration, following the same procedures described for the first generation (treated for 10 weeks prior to mating beginning at weaning).

There were two treatment

- related mortalities (one high

- dose P and one high

- dose F 1 adult female), although a total o f 7 animals died during the study. Decreased body weight occurred in high

- dose males from both generations due to decreased food consumption. F 1 females had low body weights beginning at birth through 34 days after weaning. P females had lower body weights sporadically during gestation and lactation, but F 1 females had a consistently lower body weight through gestation and lactation mainly due to the low body weight gains during gestation.

There was a dose

- dependent significant increase in absolute and r elative thyroid weights in male rats of both generations and in P female rats (mid

- and high

- dose) and F1 (high

- dose; NS) . This was accompanied by microscopic lesions in the thyroid ( altered staining of the colloid in the follicle, hypertrophy, hyperplasia and/or follicular dilatation, consistent with hypothyroidism) observed at all doses in both sexes in both generations

, males were generally more affected than females

. Relative weights of the pituitary gland were increased for all treated P males and F 1
m id

- and high

- dose males. Absolute and relative weights of the pituitary gland were increased for all treated F 1 females; microscopic lesions (hypertrophy and hyperplasia of the chromophobe cells of the pars distalis of the anterior pituitary) were observed in high

- dose animals (lower doses not examined).

There was a significant increase in relative salivary gland weights in P males. This is considered
treatment

- related as it had been noted in previous studies, but is considered of minor toxicological sign ificance due to the lack of histopathological findings. This increase was not noted in the F 1 males or in females from either generation. Absolute testes weights and epididymal weights were significantly decreased for all treated F 1 males, at a greater de gree for the mid

- and high

- dose groups, with total sperm per epididymis decreased at both the mid

- and high

- dose levels and total sperm per testis decreased at the high dose. Relative testes weights of the high

- dose F 1 males were decreased significantly. T hese weight changes of the testes and epididymis are considered to be treatment

- related, although their toxicological significance and causation are not quite clear yet.Docket Number EPA

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Page 44 of 79 The parental systemic LOAEL is 2.5 mg/kg bw/day

, based on thyroid weight increases an d thyroid histopathology changes in males and females. The parental systemic NOAEL could not be established because effects on the thyroid were observed in both genders at every dose level.

There was a decrease in offspring survival in the high

- dose group as measured by significant increases in post

- implantation loss and decreases in live birth index and viability index for both generations. There was also a decrease in lactation index that was outside the historical control range. In the F 2 generation, th ere was also a decrease in survival in the mid

- dose group. The decrease in live birth index, viability index, and lactation index did not reach statistical significance, but was outside the historical control range and is considered treatment

- related. Bod y weights were reduced in the high

- dose offspring from both generations. Gross and microscopic evaluation indicated an increase in the incidence of dilation of the renal pelvis in high

- dose offspring of both generations.

The offspring LOAEL is 10 mg/kg bw /day , based on decreased offspring survival at this level

. The offspring NOAEL is 2.5 mg/kg bw/day

. The mating indices for F 1 males and females were lower in the high

- dose compared to the controls. While the decrease was not statistically significant, it was outside of the historical control range and is considered treatment

- related. High

- dose F 1 adult males had a decrease in absolute and relative testes weight that correlated with a decreased total sperm count in the testes and epididymis (only absolut e epididymis weights were decreased). However, when measured on a gram of tissue basis, the sperm counts were similar to the control.

The reproductive LOAEL is 40 mg/kg bw/day in males and females

, based on a biologically significant decrease in male and female mating indices, female conception index, and male and female fertility indices . The reproductive NOAEL is 10 mg/kg bw/day in males and females

. This study is ACCEPTABLE/GUIDELINE and satisfies the guideline requirement for a two

generation reprod uctive study (OPPTS 870.3800); OECD 416 in rats

. 

## Chronic Toxicity / Carcinogenicity

Adequacy of D atabase for Chronic Toxicity /Carcinogenicity : The re are no (combined) chronic toxicity /carcinogenicity stud ies in the agency’s hazard database

. T hese studies are anticipated to be required for registration review risk assessment . B ased on the currently registered uses for d iiodomethyl p

- tolyl sulfone , the agency is anticipated to conduct a drinking water assessment for registration review, which may trigger the requirement of chronic toxicity /carcinogenicity studies

, for adequate ly assess i n g the risk associated with the registered uses of d iiodomethyl p

tolyl sulfone

. 

## Mutagenicity

Adequacy of D atabase for Mutagenicity : The database for mutagenicity is consider ed adequate for the currently registered uses. Several mutagenicity studies, including in vitro and in vivoDocket Number EPA

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Page 45 of 79 studies, have been submitted and reviewed by the Office of Pesticide Programs (OPP). Diiodomethyl p

- tolyl sulfone is found to be non

- mutagenic. The summaries of these studies are provided below.

Gene Mutation

(1) In a bacterial reve rse mutation assay (MRID 47307306), following a range

- finding toxicity testing with S. typhimurium tester strain TA 100 and E. coli tester strain WP2 uvr A in doses rangin g from 10.0 to 5000 μg/plate (duplicate, with/without S9 mix), d iiodomethyl p

- tolyl sulfone ( 97.4% a.i. ; Lot No. PB1631LA01) was administered, in triplicate, to cultures of S. typhimurium tester strains TA98, TA100, TA1535, and TA1537 and E. coli tester st rain WP2 uvr A at dose levels of 5.0, 10.0, 25.0, 50.0, 100, 250, and 500 μg/plate for all tester strains in the presence of S9 mix. In the absence of S9 mix, dose levels were 0.5, 1.0, 2.5, 5.0, 10, 25, and 50 μg/plate for the S. typhimurium tester strains and 2.5, 5.0, 10, 25, 50, 100, and 250 μg/plate with E. coli tester strain WP2 uvr A for the initial assay. The concentrations tested in the confirmatory assay with all S. typhimurium tester strains were 2.5, 5.0, 10, 25, 50, 100, and 250 μg/plate in the pre sence of S9 mix and 0.5, 1.0, 2.5, 5.0, 10, 25, and 50 μg/plate for the absence of S9 mix; the tested concentrations for E. coli tester strain WP2 uvr A were 5.0, 10, 25, 50, 100, 250, and 500 μg/plate both in the presence and absence of S9 mix. “The results of the Salmonella

- Escherichia coli /mammalian

- microsome reverse mutation assay pre

- incubation method with a confirmatory assay with AMICAL TM 48 indicate that under the condition of the study, the test article did not cause a positive increase in the mean nu mber of revertants per plate with any of the tester strains either in the presence or absence of microsomal enzymes prepared from Aroclor TM

- induced rat liver (S9).” A final conclusion will be reached upon completion of the a gency’s comprehensive review.

(2) In a mouse lymphoma forward mutation assay (MRIDs 00160070/94039011), the mouse lymphoma cell line, L5178Y TK + / ̵

– , were exposed to d iiodomethyl p

- tolyl sulfone (99% a.i.; Lot # 66

- 207

- CB) for four hours, in the absence and presence of rat liver S9 meta bolic activation system. D iiodomethyl p

- tolyl sulfone was assayed from 0.3 to 2.0 μg/ml (0.3, 0.5, 0.6, 0.8, 1.0, and 2.0 μg/ml) under the non

- activation conditions; the highest concentration was excessive toxic. But the remaining five lower treatments cau sed low to moderate toxicity with no significant increased mutant frequency above the background. In the presence of S9 metabolic activation, the concentrations tested (ranged from 0.5 to 5.0 μg/ml) induced a wide range of toxicity; however, no significant increases in the mutant frequency were identified. D iiodomethyl p

- tolyl sulfone did not demonstrate mutagenic potential in the mouse lymphoma
assay.
This study is classified Acceptable

. Cytogenetics

(1) D iiodomethyl p

- tolyl sulfone (96.5% a.i.; Lot # 3

- 0410) was administered to Chinese Hamster Ovary (CHO) cells cultures at dose levels of 0.125, 0.25, 0.5, 1, 2, and 4 μg/ml in the

non

- activated study and at 0.5, 1, 2, 4, 8, and 16 μg/ml in the S

- 9 activated study (MRIDDocket Number EPA

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Page 46 of 79 43120601). At the highest doses, the re were sufficient indications of a cytotoxic response (reduction in mitotic index). Under the condition of this assay, there was no indication of a positive clastogenic and/or aneugenic response in the absence (harvested at 18 hours) or S

- 9 activation (ha rvested at 12 hours). D iiodomethyl p

- tolyl sulfone ( Amical ® 48 Preservative ) was concluded to be negative in the chromosome aberrations in Chinese Hamster Ovary cells (CHO) cells cytogenetics assay.

This study is classified A cceptable /Non

- guideline and sa tisfies the Guideline requirement for a structural chromatic aberration assay (OCSPP 870.5375).

(2) In an in vivo mouse micronucleus assay (MRIDs 00160071), d iiodomethyl p

- tolyl sulfone (99% a.i.; Lot # 66

- 207

- CB) was administered, at concentrations of 0. 5, 2.5, and 5.0 g/kg (based on an oral LD 50 ), to 5 ICR mice/sex/group intraperitoneally (i.p.) by individual weight with volumes based on 10 ml/kg. Animals were dosed on an acute regimen with groups killed 24, 48, and 72 hours post

- dosing. The negative and positive control groups were killed 24 hours after dosing. An additional group of 5 mice/sex were treated with 5.0 g/kg dose concentration and were only used to replace animals which died in the primary dose groups. Bone marrow cells were harvested at th e sacrificing schedule stated above ( 24, 48, and 72

- hours post

- treatment). The positive control was triethylenemelamine (TEM) used at 1.5 mg/kg, administered by one i.p. injection. D iiodomethyl p

- tolyl sulfone did not induce toxic signs in any animals, nor did positive or negative controls.

No significant increases in number of micronucleated polychromatic erythrocytes (MN

- PCEs) frequencies were reported in any dose group ov er the negative control animals, whereas a significant increase in the frequenci es of MN

- PCEs was observed in the positive control group. The mean percent PCE values were significantly reduced at 500 mg/kg and for the positive control groups compared to the c orresponding negative controls. D iiodomethyl p

- tolyl sulfone did not demons trate mutagenic potential in the mouse bone marrow micronucleus assay under the test condition.

This study is classified Acceptable

. Other Genotoxicity

(1) In an in vitro primary rat hepatocyte unscheduled DNA synthesis (UDS) assay (MRIDs 00160072/94039 012), fresh hepatocytes from rat liver were exposed to d iiodomethyl p

- tolyl sulfone (99% a.i.; Lot # 66

- 207

- CB) at concentrations ranged from 0.052 to 5.19 μg/mL. The positive control used was a

- acetylaminofluorene (2

- AAF) at 0.05 and 0.10 μg/mL; the test material solvent served as the negative control.

. No significant increases in mean net nuclear grains (NNG), or in the percent of nuclei with six or more net grains, were reported at any dose level at any time point. This was comparable to the solvent controls. There was no evidence of induction of unscheduled DNA synthesis in rat primary hepatocytes over the background. The positive control elicited a clear positive response. It was concluded that, under the condition of the present test, d iiodomethyl p

- tolyl sulfone didDocket Number EPA

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Page 47 of 79 not demonstrate mutagenic potential in the present in vitro primary rat hepatocyte unscheduled DNA synthesis (UDS) assay.

This study is classified Acceptable

.



## Neurotoxicity

870.6200 Neurotoxicity Screening Battery

Adequacy of Datab ase for Neurotoxicity: The database for neurotoxicity is considered incomplete. There are no neurotoxicity studies in the agency’s hazard database. A neurotoxicity screening battery is anticipated to be required for registration review risk assessment, based on the currently regi stered uses for DIMTS

. 

## Immunotoxicity

870.7800 Immunotoxicity Study

Adequacy of Database for Immunotoxicity: The database for immunotoxicity is considered incomplete . There are no immunotoxicity studies in the a gency’s hazard dat abase. An immunotoxicity study is anticipated to be required for registration review risk assessment

, based on the currently registered uses for d iiodomethyl p

- tolyl sulfone

. 

## Other Toxicological Effects

Metabolism and Pharmacokinetics

In a metabolism stu dy (MRID 47076 6 01)

, Amical TM 48 Antifungal Agent (1

- ((diiodomethyl)sulpfonyl)

- 4

- methyl benzene, ; 97.7% a.i., L ot no. 172

- 015

- 032) and 14 C

- Amical methyl substituted to the aromatic ring was radiolabeled; 99.8% a.i., L ot no. PB1631LA01 ) was administered to F isher 344 or Sprague

- Dawley rats following the exposure schemes described below. Five oral absorption

, distribution , and elimination studies in F

- 344 rats were performed each using 4 rats/sex/dose at target dose levels of 5.0 or 50 mg/kg. In these studies a single oral dose was administered via gavage at calculated doses of 5.0 mg/kg (Groups 1, 3, and 5 ; actual concentrations were for Group 1, 5.03 mg/kg in males and 5.02 females; Group 3, 5.26 mg/kg in males and 5.14 females; Group 5, 5.06 mg/kg in males and 5.13 females ) or 50 mg/kg (Groups 2 and 4 ; actual concentrations were for Group 2, 51.44 mg/kg in males and 51.19 mg/kg in females; Group 4, 51.09 mg/kg in males and 51.99 mg/kg in females ). In a multi

- dosing study, animals were administered 5.0 mg/kg unlabeled Amical TM 48 (actual concentration was not determined for unlabeled Amical TM 48 ) via the diet for 14 days, then dosed with a comparable single oral dose of radio labeled Amical TM 48 via gavage (Group 6 ; actual concentrations were 5.10 mg/kg in male s and 4.96 mg/kg in females). A single 6 hour dermal dose was utilized with both males and females (Group 8) receiving 5.0 mg/kg 14 C

- Amical TM 48 , the actual measure doses were 6.99 mg/kg in males and 9.14 mg/kg in females; volatility studies showed thatDocket Number EPA

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Page 48 of 79 am bient temperatures did not cause dermal doses of Amical TM 48 to dissipate. A single oral dose of 5.0 mg/kg 14 C

- Amical TM 48 (actual concentration 5.04 mg/kg) was given to 4 Sprague

Dawley females (Group 7 ). Metabolite distribution was determined in Groups 1, 2, 5, 7, and 8 (Group 8 excreta had metabolite concentrations too low to analyze) from urine and plasma; free iodine was determined in all Groups. Pharmacokinetic parameters were determined in Groups 1, 2, 7, and 8.

After a single oral dose of 5.0 or 5 0 mg/kg 14 C

- Amical TM 48 , the maximum concentration of Amical TM 48 (C max ) in the blood is reached within an 15 minutes at the low dose and 30 minutes for the high dose , and the plasma half

- life at the low doses were between 1

- 2 hours and a 2

- fold increase w as noted at the high dose with a plasma half

- life of 2

- 4 hours; oral dose was available in a dose proportionate manner

. Plasma radioactivity levels were non

- detectible after 24 hours except in the high

- dose males that were non

- detectable the next day, this coincides with higher levels of glutathione conjugated parent compound observed in the males. Free iodine elimination was slower than the rapid elimination of the radiolabeled Amical TM 48 equivalent; the half

- life of free iodine was approximately 2.5 hour s in the low oral doses and 4

- 5 hours in the high oral dosed F344 rats. No difference in absorption, route of elimination, or pharmacokinetics were observed when comparing F344 rats and Sprague

- Dawley rats; however, the Sprague

- Dawley rats displayed a decr eased elimination of free iodine, with a plasma half

- life of 7 hours, a 3 fold increase over the F344 rats dosed at the same rate of 5 mg/kg. The maximum concentration (C max ) and time to maximum concentration (t max ) was the same in F344 and Sprague

- Dawley rats, but the area under the curve (AUC) and half

- life (t 1/2 ) were longer suggesting greater bioavailability of iodine in the Sprague

- Dawley rats. Radioactivity elimination in Sprague

Dawley rats was comparable to F344 rats.

After multiple doses of unlabe led Amical TM 48 , one dose of radioactive Amical TM 48 displayed no difference in absorption, elimination, pharmacokinetics, metabolism, or route of elimination. Dermal Amical TM 48 was absorbed 7

- 10% of the applied dose; plasma radioactivity and iodine

were negligible, 5

- 7% were found in the urine and fecal elimination was <0.3%. The dermal dose was slowly absorbed and rapidly eliminated mainly in the urine with 23

- 30% of the absorbed dose in the urine after 24 hours and 38

- 45% after 48 hours. The dermal appl ication site wash was the major depot of radioactivity with 80% rinsed off the males and 90% in females. The application site had 1.1 and 2.4% of the applied dose, in males and females, respectively; stratum conrneum (tape strips) had 0.1

- 0.2% of the appli ed dose. Tissues had 0.3% of the applied dose or 3

- 5% of the absorbed dose at the end of the study. Recoveries were between 90

- 97%.

The major route of elimination was through the urine for all exposure methods with 87

- 97 % excreted and most was within the first six hours (78

- 92%) ; elimination in the feces accounted for 7

- 13 % of the radioac tivity. Organ/tissue radioactivity levels were <1% of the dose received after 7 days, this also included the plasma. Results indicate that orally administered Amical TM 48 is rapidly and almost completely absorbed from the gastro

- intestinal tract and eliminated quickly. Expired air and volatiles was not a major route of elimination, negligible findings were noted in all air traps.

Distribution patterns in the orally dosed animals were similar between the single

- and repeat

dosed Groups with the highest residual radioactivity found in the major elimination organs/tissue, i.e., the kidney, liver, and plasma; however, the levels were low. No organDocket Number EPA

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Page 49 of 79 demonstrated accumulation of Amical TM 48 with highest levels of Amical TM 48 equivalent in the plasma 7 days after dosing. The plasma, kidney, and liver eliminates Amical TM 48 equivalent rapidly with most of the concentration eliminated by the 6 th hour

. Upon absorption, iodine is lib erated from the Amical TM 48 reaching maximum concentration at 4 hours in the low

- dose groups and 2 hours in the high

- dose groups. Elimination of iodine is slower than the radioactive portion of Amical TM 48 , with 9

- 13% of free iodine in the urine and 5

- 7% o f the radioactivity in the urine. The total free iodine detected in the urine was 59

- 73% and 41

- 43% of the total radioactivity, in low

- and high

- dose groups, respectively. Fecal iodine elimination was between 7

- 13% and most was within the first 24 hours. Dermal exposures produced an iodine profile in the urine that was different than oral exposures; the total amount of iodine in the urine was higher than oral exposure groups, indicating a higher metabolism of one or both of the iodine groups from DIMTS

.

I n the blood and excreta analyzed for metabolites, no parent compound was found. T he major metabolites were the parent conjugated with glucuronide and 3 non

- parent oxidated benzylic methyl moiety or minor ring hydroxylation. Two major metabolites in the blo od, in order of concentration, were p

- iodomethylsulphone benzoic acid and p

- methylsulfone benzoic acid. Major metabolites in the urine for the low

- dose group, in order of concentration, were p

methylsulfone benzoic acid, p

- iodomethylsulphone benzoic acid, and methyl

- p

- tolylsulpfone, which accounted for 62

- 88% of the dose; whereas, p

- iodomethylsulphone benzoic acid, p

methylsulfone benzoic acid, and methyl

- p

- tolylsulpfone (in order of concentration), which accounted for 75

- 88% of the dose, were the major met abolites in the urine for the high

- dose group. Major fecal metabolites were p

- methylsulfone benzoic acid and p

- iodomethylsulphone benzoic acid, which accounted for 5

- 9% of the dose.

This metabolism study in the rat is classified ACCEPTABLE / GUIDELINE and satisfies the guideline requ irement for a metabolism study ( OPPTS 870.7485 ; OECD 417 ) in rats.

Dermal Penetration Study

There is no acceptable guideline dermal penetration study. There is some dermal absorption information in the pharmacokinetics and met abolism study (MRID 47076601) summarized above.

In the pharmacokinetics and metabolism study (MRID 47076601), 4 Fischer 344 rats/sex (Group 8) dermally received a single dose of 14 C

- diiodomethyl p

- tolyl sulfone on the shaved back (between scapula). The ap plication site was covered with mesh and was washed 6 hours after application. Dose suspension for the dermal application was prepared at the target concentration of ~ 8.8 mg/ml and applied at a dose volume of 10 μl/cm 2 to 12 cm 2 , which resulted in a dose of ~ 5 mg/kg ( the actual measure doses were 6.99/9.14 mg/kg in males/females ). Volatility studies showed that ambient temperatures did not cause dermal doses of 14 C

- diiodomethyl p

- tolyl sulfone to dissipate . Absorption of the dermally applied diiodomethyl p

- tolyl sulfone was 7

- 12% of the dose. The dermally applied dose was slowly absorbed from the site of application and rapidly eliminated in urine accounting for 23

- 30% and 38

- 45% of the absorbed dose within 24 hours and 48 hours, respectively. Between 5 an d 7% of the applied dose was excreted in urine, fecal elimination was negligible (~0.3%). The level of radioactivity and free iodide in the plasmaDocket Number EPA

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Page 50 of 79 of the dermally dosed animals remained below the level of quantification ( < LOQ ) throughout the study. The to tal amount of iodide found in the urine of the dermally dosed rats was 10

- 40% higher than the total radioactivity, which was opposite to what was observed in the orally dosed animals, indicating higher metabolism/liberation of one or both of the iodide fro m the parent molecule. Elimination of radioactivity and iodide in urine continued during the analysis period due to slow continuous absorption of 14 C

- diiodomethyl p

- tolyl sulfone from the application site. It is anticipated to have variations ranging from 90

- 110% recovery rates for the dermal absorption study. Therefore, the a gency concluded that the appropriat e dermal absorption factor in the risk assessment should be approximately 10%.Docket Number EPA

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Page 51 of 79 Table A 2

– Toxicity Profile for DIMTS

Guideline No./

Study Type MRID No./ Study Classification Dosing and Animal Information Results
Subchronic Toxicity 870.3100 90

- day Oral (Rat) MRID 4205 4402 /43246401

Core

- Minimum Purity 95 %

Crl:CD (SD)BR rats (10 /sex/ dose)

0, 5, 2 0, or 8 0 (15/sex) mg/kg/d , in diet, for 90

- 94 days

. N OAEL ≥ 80 mg/kg/d The only significant findings in the treated animals were statistically significant elevations in mean phosphorus and cholesterol levels in the high dose group males and squamous metaplasia of the salivary gland ducts in three males in th e high dose group. All of the effects noticed in the treatment groups were not considered toxicologically significant. The highest dose does not reach the maximum tolerated dose (MTD).
870.3100 90

- day Oral (Rat) MRID 4 7338201

U n der a gency review Purity 9 7.4%
Sprague

- Dawley (CD) (8

r ats / sex/ d o se)

0, 5, 20, 10 0, or 2 5 0 mg/kg/d, in diet, for at least 13 weeks The study author concluded:

N OAEL = 20 mg/kg/d , based on hyperplasia of the non

- glandular mucosa of the stomach and squamous metaplasia of the saliv ary glands at 10 0 mg/kg/d
870.31 50 90

- day Oral ( Dog ) MRID 4 2 05 4403/43246402

Core

- Minimum Purity 95 %
Beagle dog s (4/ sex/ group)

0, 2, 1 0 , or 6 0 mg/kg/day , in gelatin capsules, for 9 6

- 100 days NOAEL = 2 mg/kg/day LOAEL = 10 mg/kg/day

, based on histopatho logical changes observed in the thyroid glands ( deg eneration of the thyroid gland [ mineralization within colloid clumping of sloughed follicular cells and colloid depletion ] ), salivary gland ( Sialadenitis [ ductal and periductal inflammation of the salivar y gland]) and gastrointestinal (GI) tract ( hemorrhagic gastritis, necrosis of the small intestine and keratitis )

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Page 52 of 79 Guideline No./

Study Type MRID No./ Study Classification Dosing and Animal Information Results

870.3200 21/28 day dermal (rats) MRID 48 2369 01

Acceptable/Guideline Purity 9 4 .6%

Crl:CD (SD)BR rats (10 /sex/ dose)

0, 2 0, 100, or 50 0 mg/kg /d ay, semi

- occlusion, 6 hr/day, 7 days/wk, for 28 consecutive days. NOAEL systemic = 20 mg/kg/day (♀) and not established for males LOAEL systemic = 100 mg/kg/day (♀)

, based on thyroid effects ( very slight hypertrophy of thyroid follicular epithelial cells and altered tinctorial properties of the colloid, characterized by the presence of pale to very pa le eosinophilic colloid in the follicles )

. NOAEL dermal = 20 mg/kg/day LOAEL dermal = 100 mg/kg/day

, based on multifocal scabs, slight epidermal hyperplasia (acanthosis) with very slight parakeratosis, and very slight multifocal subacute to chronic inflamma tion in the dermis

. 870.3465 90

- day inhalation Subchronic (Rat ) MRID 48264901

Acceptable/Guideline Purity 97.3 %

Crl:CD(SD) rats (10/sex/concentration)

0, 1, 7, or 30 mg/m 3 , nose only, 6 hr/d, 5 days/wk, for 13 wks (65 total exp. days). The average mass median aerodynamic diameter (MMAD) of the test material aerosol was 2.6

, 2.7

, and 2.6 μm for exposure concentration groups 1, 7, and 30
mg / m 3 , respective l y. NOAEC = 1 mg/m 3 LOAEC = 7 mg/m 3 , based on
treatment

- related systemic effects were observed in the thyroid glands (colloid with altered tinctorial properties) and unilateral or bilateral parakeratosis with inflammation in the anterior nasal cavity in both male and female rats.

Developmental Toxicity 870.3700a Developmental Toxicity (Rat) MRIDs 420544 04/42054405/ 43246403

Core

- Guideline Purity 95 %

Crl:CD(SD) albino rats (22/group)

0, 10 0, 30 0, or 100 0 mg/kg/d ay , oral gavage, gestation days ( GD ) 6

- 15

For MRID 42054405 :
Crl:CD(SD) albino rats (25/group)

0 or 100 0 mg/kg/d ay , oral gavage, gestation d ays ( GD ) 6

- 15 NOAEL maternal = 1 0 0 mg/kg/d LOAEL maternal = 3 0 0 mg/kg/d

, based on ↓ body weight gain and food consumption.

NOAEL developmental = 30 0 mg/kg/d LOAEL developmental = 1000 mg/kg/d

, based on ↓ mean litter size, ↑ number of resorptions relative to the number of implantation sites, ↓ mean fetal body weight, ↑ incidences of umbil ical hernia, and incomplete ossification of the supraoccipital bones.Docket Number EPA

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Page 53 of 79 Guideline No./

Study Type MRID No./ Study Classification Dosing and Animal Information Results

870.3700a Developmental Toxicity (Rat) MRIDs 47373805

U n der a gency review Purity > 95 %

Wistar rats (22/group)

0, 0 .125 , 0 .25

, 0.5, or 1.0% (estimated daily intakes of test material 0 , 100, 182, 288, or 411 mg/kg/d, respectively)

, in the diet, gestation days ( GD ) 6

- 15 Significant lower maternal body weight gain and food consumption were observed in the three higher dose groups

. No significant changes induced by the test substance were detected in the numbers of resorption, fetal death, or body weight of live fetuses. No evidence of teratogenesis was revealed in fetuses during morphological examination.
870.3700b Developmental Toxicity (Ra bbi t) MRIDs 42243801/43246404

Core

- Supplementar y Purity 9 5 %

Pregnant New Zealand White rabbits 0, 4, 15, or 60 mg/kg/day, oral gavage, gestation day (GD) 6

- 18, inclusive NOAEL maternal = 4 mg/kg/d LOAEL maternal = 15 mg/kg/d , based

on clinical signs (deaths) and ↓ body weight gain and food consumption

NOAEL developmental < 4 mg/kg/d (not established) LOAEL developmental ≤ 4 mg/kg/d

, based on increased fetal and litter incidence of unossified olecranon and unossified sternebrae
870.3700b Developmental Toxicity (Ra bbi t) MRID 47242202

Acceptable/Guideline Purity 97.7%

26 rabbits/dose

0, 0.05, 0.5, or 2.0 mg/kg/day

, gavage, gestation days (GD) 7

- 27 NOAEL maternal = 2 mg/kg/d (HDT) L OAEL maternal not established.

NOAEL developmental = 2 mg/kg/d (HDT) L OAEL development al not established.
870.3700b Developmental Toxicity (Ra bbi t) MRIDs 47214601

U n der a gency review Purity 97.7%

New Zealand White rabbits (7 /dose )

0, 1, 4, 8, or 15 mg/kg /day , gavage, gestation days 7

- 27 NOAEL maternal < 1 mg/kg/d (LDT) L OAEL maternal = 1 mg/kg/d , based on ↑ in absolute and relative thyroid gland weights with corresponding thyroid follicle dilatation (slight to moderate) and distension with colloid at all tested dose levels.

NOAEL developmental = 4 mg/kg/d (HDT) LOAEL developmental = 8 m g/kg/d

, based on higher incidence of post

implantation loss (26.4% and 20.6%, respectively vs. 4.6% in control), which corresponded with increases in resorptions per litter and litters with resorptions, and decreases in litter size.

The a gency will reach a final conclusion after a comprehensive review of the study. Reproduction ToxicityDocket Number EPA

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Page 54 of 79 Guideline No./

Study Type MRID No./ Study Classification Dosing and Animal Information Results

870.3800 Reproduction MRID 4 69 1 33 0 2

Una cceptable/Guideline Purity 97.4%

Sprague

- Dawley Crl:CD [SD] IGS BR rats (30 /sex/dose group )

0, 20, 80, or 200 mg/kg/day (adjus ted time

- weighted average of 0/0, 21.8/20.7, 86.1/82.0, or 213.9/204.0 mg/kg/day in males/females, respectively), in diet, for approximately ten weeks prior to mating to produce the F1 litters.

This study was originally designed
as a two

- generation repro ductive toxicity study, but was terminated during F1 littering due to high mortality in pups of the two highest treatment groups. NOAEL parental < 5 mg/kg/d (not established) LOAEL parental = 20 mg/kg/d (adjusted time

- weighted average of 21.8/20.7 mg/kg/day in males/females)

, based on decreased body weights, body weight gains, and food consumption in the males and clinical signs of toxicity (red perinasal soiling that occurred around parturition in the females).

NOAEL offspring < 20 mg/kg/d (not established); LOAEL offspring = 20 mg/kg/d

, based on decreased body weights at all levels.

NOAEL reproductive = 20 mg/kg/d ( ♀ ) LOAEL reproductive = 80 mg/kg/d ( ♀ )

, based on decreased gestation survival index. There were no treatment

related toxic effects in males at any dose level, so a reproductive LOAEL for males cannot be calculated 870.3800 Reproduction MRID 46913301

A cce ptable/Guideline Purity 97.4%

Sprague Dawley rats (30 /sex/group )

0, 2.5, 10, or 40 mg a.i./kg/day , in diet, for two successive generations (P: approx. 10 weeks prior to mating to produce the F1 litters. All litters were weaned on PND 21, and one F1

wean ling/sex/litter was randomly selected to be a parent of the next generation and treated for 10 weeks prior to mating beginning at weaning). NOAEL parental < 2.5 mg/kg/d ( not established ) LOAEL parental = 2.5 mg/kg/d, based

on ↑ thyroid weight increases and thyroid histopatholog y changes in males and females at every dose level.

NOAEL offspring = 2.5 mg/kgd LOAEL offspring = 10 mg/kg/d , based

on decreased offspring survival

.

NOAEL reproductive = 1 0 mg/kg/d LOAEL reproductive = 40 mg/kg/d

, based on a biologically significant ↓ in male and female mating indices

, female conception index, and male and female fertility indices

. Chronic Toxicity 870.4100 Chronic Toxicity A chronic toxicity study is not available for DIMTS

.

Carc inogenicity 870.4200 Carcinogenicity A carcinogenicity study is not available for DIMTS

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Page 55 of 79 Guideline No./

Study Type MRID No./ Study Classification Dosing and Animal Information Results

870.5100 Bacterial reverse mutation test MRID 4 7307306

U n der a gency review Purity 97.4 %

S. typhimurium TA98, TA100, TA1535, and TA1537 and E. coli WP2 uvr A

T he initial assay : 5.0, 10.0, 25.0, 50.0, 100, 250, and 500 μg/plate for all tester strains (+S9); 0.5, 1.0, 2.5, 5.0, 10, 25, and 50 μg/plate for the S. typhimurium tester strains (

- S9) and 2.5, 5.0, 10, 25, 50, 100, and 250 μg/plate with E. col i WP2 uvr A (

- S9) for.

The confirmatory assay : S. typhimurium tester strains

– 2.5

, 5.0, 10, 25, 50, 100, and 250 μg/plate (+S9) and 0.5, 1.0, 2.5, 5.0, 10, 25, and 50 μg/plate (

- S9) E. coli WP2 uvr A

– 5.0 , 10, 25, 50, 100, 250, and 500 μg/plate (+/

- S9 ) T he study author concluded that “The results of the Salmonella

Escherichia coli /mammalian

microsome reverse mutation assay
pre

- incubation method with a confirmatory assay with AMICAL TM 48 indicate that under the condition of the study, the test article did n ot cause a positive increase in the mean number of revertants per plate with any of the tester strains either in the presence or absence of microsomal enzymes prepared from Aroclor TM

- induced rat liver (S9).”

870.5300 Mammalian cell gene mutation test MRID s 00160070/94039011

Acceptable Purity 99 %

mouse lymphoma cells (L5178Y TK +/

- )

0.3

– 2.0 μg/ml (0.3, 0.5, 0.6, 0.8, 1.0, and 2.0 μg/ml) (

- S9) and 0.5

– 5.0 μg/ml (+S9), for a period of 4 hours Nega tive

870.5300 Mammalian cell gene mutation test MRID 4 3120601

Acceptable/Non

guideline Purity 94.5%

Chinese hamster ovary (CHO) cells

0.125, 0.25, 0.5, 1, 2, and 4 μg/ml (

- S9) and 0.5, 1, 2, 4, 8, and 16 μg/ml (+S9) Negative

870.5385 In vivo mouse micronucleus
assay MRID 00160071

Acceptable Purity 99 %

I CR mice (5/sex/group)

0.5, 2.5, and 5.0 g/kg (based on an oral LD 50 ), intraperitoneally (i.p.), by individual weight with volumes based on 10 ml/kg. Animals were killed and bone marrow cells at 24, 48, and 72 hours post

- dosing. The negative and positive c ontrol groups were killed 24 hours after dosing. NegativeDocket Number EPA

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Page 56 of 79 Guideline No./

Study Type MRID No./ Study Classification Dosing and Animal Information Results

870.5550 ( I

n vi tr o ) Unscheduled DNA synthesis MRID s 00160072/94039012

Acceptable Purity 99 %
Rat hepatocyte cells
0.052 to 5.19 μg/mL. The positive control used was a

acetylaminofluorene (2

- A AF) at 0.05 and 0.10 μg/mL; the test material solvent served as the negative control Negative

870.5550 Unscheduled DNA synthesis MRID 41298503

A cceptable Purity 81 %

Rat (male) hepatocyte cells

5x10

- 7

– 1x10

- 3 m L/mL Negative

870.6200 Neurotoxicity

scre ening battery A neurotoxicity screening battery is not available.

870.7800 Immunotoxicity An immunotoxicity study is not available

.

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Page 57 of 79

870.7485 M etabolism and Pharmacokinetics MRID 47076601

Acceptable/Guideline Purity 99.8% (radiolabeled); 97.7 % (non

- radiolabeled)

Fisher 344 or Sprague

- Dawley rats (4/dose group)

Exposure schemes:

- S ingle oral dose: 5.0 mg/kg 14 C

Amical TM 48 (actual conc . [♂/♀]: 5.03 /5.02 ; 5.26 /5.14; and 5.06 /5.13 mg/kg for Groups 1, 3, and 5, respectively) or 50 mg/kg 14 C

Amical TM 48 (actual conc . [♂/♀]: 51.44 /51.19 and 51.09 /51.99 mg/kg for Groups 2 and 4, respectively ), via gavage

- M ulti ple oral d os es ( Group 6 ) : 5.0 mg/kg unlabeled Amical TM 48 (actual conc

. not determined), via the diet, for 14 days ; then dosed with a comparable single oral dose of 14 C

- Amical TM 48 via gavage (actual conc

. [♂/♀]: 5.10 /4.96 mg/kg) ;

- S ingle dermal dose (Group 8) : 5.0 mg/kg 14 C

- Amical T M 48 (actual measure doses [♂/♀]: 6.99 / 9.14 mg/kg ) for 6 hr ;

- S ingle oral dose (Group 7) : 5.0 mg/kg 14 C

- Amical TM 48 (actual

conc .: 5.04 mg/kg) given to 4 Sprague

- Dawley females

Metabolite distribution was determined in Groups 1, 2, 5, 7, and 8 (Group 8 excreta had metabolite concentrations too low to analyze) from urine and plasma; free iodine was determined in all Groups. Pharmacokinetic parameters were determined in Groups 1, 2, 7, and 8. After a single oral dose of 14C

- AmicalTM 48, the plasma concen trations peaked (Cmax) within15 minutes and 30 minutes for the low dose (5 mg/kg) and the high dose (50 mg/kg), respectively, and the plasma half

- life at the low doses were between 1

- 2 hours and 2

- 4 hours (2

- fold increase) at the high dose. Plasma radioact ivity levels were non

- detectible after 24 hours except in the high

- dose males that were non

- detectable the next day, this coincides with higher levels of glutathione conjugated parent compound observed in the males. Free iodine elimination was slower than the rapid elimination of the radiolabeled AmicalTM 48 equivalent; the half

- life of free iodine was approximately 2.5 hours in the low oral doses and 4

- 5 hours in the high oral dosed F344 rats.

No difference in absorption, route of elimination, or pharmac okinetics were observed when comparing F344 rats and Sprague

- Dawley rats; however, the Sprague

- Dawley rats displayed a decreased elimination of free iodine, with a plasma half

- life of 7 hours, a 3 fold increase over the F344 rats dosed at the same rate of 5 mg/kg. The maximum concentration (Cmax) and time to maximum concentration (tmax) was the same in F344 and Sprague

- Dawley rats, but the area under the curve (AUC) and half

- life (t1/2) were longer, suggesting greater bioavailability of iodine in the Spragu e

- Dawley rats. Radioactivity elimination in Sprague

- Dawley rats was comparable to F344 rats.

After multiple doses of unlabeled AmicalTM 48, one dose of 14C

AmicalTM 48 displayed no difference in absorption, elimination, pharmacokinetics, metabolism, or ro ute of elimination.

Dermal 14C

- AmicalTM was absorbed 7

- 10% of the applied dose; plasma radioactivity and iodine were negligible, 5

- 7% were found in the urine and fecal elimination was <0.3%. The dermal dose was slowly absorbed and rapidly eliminated mainly in the urine with 23

- 30% of the absorbed dose in the urine after 24 hours and 38

- 45% after 48 hours. The dermal application site wash was the major depot of radioactivity with 80% rinsed off the males and 90% in females. Tissues had 0.3% of the applied do se or 3

- 5% of the absorbed dose at the end ofDocket Number EPA

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Page 58 of 79 the study. Recoveries were between 90

- 97%.

The major route of elimination was through the urine for all exposure methods with 87

- 97% excreted and most was within the first six hours (78

- 92%); elimination in th e feces accounted for 7

- 13% of the radioactivity. Organ/tissue radioactivity levels were <1% of the dose received after 7 days, this also included the plasma. Results indicate that orally administered Amical TM 48 is rapidly and almost completely absorbed f rom the gastro

- intestinal tract and eliminated quickly. Expired air and volatiles was not a major route of elimination.

Distribution patterns in the orally dosed animals were similar between the single

and repeat

- dosed Groups with the highest residual ra dioactivity found in the major elimination organs/tissue, i.e., the kidney, liver, and plasma; however, the levels were low. No organ demonstrated accumulation of Amical TM 48 with highest levels of Amical TM 48 equivalent in the plasma 7 days after dosing. The plasma, kidney, and liver eliminates Amical TM 48 equivalent rapidly with most of the concentration eliminated by the 6 th hour.

Upon absorption, iodine is liberated from the Amical TM 48 reaching maximum concentration at 4 hours in the low

- dose
groups and 2 hours in the high

- dose groups. Elimination of iodine is slower than the radioactive portion of Amical TM 48, with 9

- 13% of free iodine in the urine and 5

- 7% of the radioactivity in the urine. The total free iodine detected in the urine was 59

- 73% an d 41

- 43% of the total radioactivity, in low

- and high

- dose groups, respectively. Fecal iodine elimination was between 7

- 13% and most was within the first 24 hours. Dermal exposures produced an iodine profile in the urine that was different than oral
exposu res; the total amount of iodine in the urine was higher than oral exposure groups, indicating a higher metabolism of one or both of the iodine groups from Amical TM 48.

14 C

- Amical TM 48 was highly metabolized

. No parent compound was identified in the blood a nd excreta

. The major metabolites were the parent conjugated with glucuronide and 3 non

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Page 59 of 79 Guideline No./

Study Type MRID No./ Study Classification Dosing and Animal Information Results
parent oxidated benzylic methyl moiety or minor ring hydroxylation.Docket Number EPA

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Page 60 of 79 Toxicology References for Appendix A

MRID

00123023 Kesterson, J.: Majors, K.; Moore, L .; et al. (1976) Acute Dermal Toxicity of DIMTS (Dry Powder) and an DIMTS Dispersion in Rabbits: Study Nos. 76

- 245 and 76

- 246. (Unpublished study received Jun 16, 1976 under 275

- 30; submitted by Abbott Labora

- tories, North Chicago, IL; CDL:225439

- A)

.
0008 7842 Horath, L.L. (1975) Report to Abbott Laboratories: Acute Vapor Inhalation Toxicity Study with DIMTS Solution in Albino Rats: IBT No. 663

- 07250. (Unpublished study received Dec 18, 1981 under 275

- 41; prepared by Industrial Bio

- Test Laboratories, Inc., submitted by Abbott Laboratories, North Chicago, Ill.; CDL:246501

- E)

. 41765401 Kreuzmann, J. (1990) Acute Oral Toxicity in Rats

- Limit Test: DIMTS : Lab Project Number: 90

- 4015

- 21 A. Unpublished study pre

- pared by Hill Top Biolabs, Inc. 14 p.

41765402 Kreuz mann, J. (1990) Primary Eye Irritation Study in Rabbits: DIMTS : Lab Project Number: 90

- 4015

- 21 C. Unpublished study prepared by Hill Top Biolabs, Inc. 15 p.

41765403 Kreuzmann, J. (1990) Primary Skin Irritation Study in Rabbits: DIMTS : Lab Project Number: 90

- 4015

- 21 B. Unpublished study prepared by Hill Top Biolabs, Inc. 14 p.

42054402 Dudley, R. (1986) Three

- Month Toxicity Study of DIMTS Administ

- ered Via the Diet to Rats: Lab Project Number: TA85

- 096. Unpub

- lished study prepared by Abbott Labs. 206 p.

4 2054403 Creighton, J. (1986) Three

- Month Toxicity Study of DIMTS Admin

- istered Orally to Dogs: Lab Project Number: TB85

- 158. Unpubli

- shed study prepared by Abbott Labs. 194 p.

42054404 Lehrer, S. (1985) Evaluation of the Effects of Orally Administered DI MTS on the Embryonic and Fetal Development of the Rat: Segment II, TFR: Lab Project Number: TE85

- 022. Unpublished study prepared by Abbott Labs. 56 p.

42054405 Lehrer, S. (1986) Evaluation of the Effects of Orally Administered DIMTS on the Embryonic and Fe tal Development of the Rat: Segment II, TFR: Supplement to Study TA85

- 022: Lab Project Numb

- er TE85

- 230. Unpublished study prepared by Abbott Labs. 33 p.

42243801 Lehrer, S. (1985) Evaluation of the Effects of Orally Administered DIMTS on the Embryonic an d Fetal Development of the Rabbit

-- Segment II, TFR: Lab Project Number: TE85

- 054. Unpublished study prepared by Abbott Labs. 64 p.Docket Number EPA

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Page 61 of 79 43008702 Kreuzmann, J. (1990) Acute Oral Toxicity in Rats

-- Limit Test of DIMTS : Supplemental Information: Lab Project Number: 90/4015/21/A. Unpublished study prepared by Hill Top Biolabs, Inc. 17 p.

43008703 Kreuzmann, J. (1990) Primary Eye Irritation Study in Rabbits of DIMTS : Supplemental Information: Lab Project Number: 90/4015/21/C. Unpublished study prepared by Hill Top Bio labs, Inc. 19 p.

43008704 Kreuzmann, J. (1990) Primary Skin Irritation Study in Rabbits of DIMTS : Supplemental Information: Lab Project Number: 90/4015/21/B. Unpublished study prepared by Hill Top Biolabs, Inc. 16 p.

43120601 Putman, D.; Curry, P.; Schadly , E. (1994) Chromosome Aberrations in Chinese Hamster Ovary (CHO) Cells ( DIMTS Preservative): Final Report: Lab Project Number: TD585/337. Unpublished study prepared by Microbiological Associates, Inc. 30 p.

43246401 Dudley, R.; Bollmeier, A. (1986) Three

- Month Toxicity Study of DIMTS Administered via the Diet to Rats: Supplemental Data: Lab Project Number: TA85/096. Unpublished study prepared by Abbott Labs. 25 p.

43246402 Creighton, J.; Bollmeier, A. (1986) Three

- Month Toxicity Study of DIMTS Administered Orally to Dogs: Supplemental Data: Lab Project Number: TB85/158. Unpublished study prepared by Abbott Labs. 22 p.

43246403 Lehrer, S.; Bollmeier, A. (1985) Evaluation of the Effects of Orally Administered DIMTS on the Embryonic and Fetal Development of the Rat

-- Segment II, TFR: Supplement: Lab Project Number: TE85/022. Unpublished study prepared by Abbott Labs. 188 p.

43246404 Lehrer, S.; Bollmeier, A. (1985) Evaluation of the Effects of Orally Administered DIMTS on the Embryonic and Fetal Development of the Rabbit

-- Segment II, TFR: Supplement: Lab Project Number: TE85/054. Unpublished study prepared by Abbott Labs. 179 p.

43660901 Wnorowski, G. (1995) Amical: Acute Inhalation Toxicity Defined LC50 (in Rats): Lab Project Number: 3515. Unpublished study pr epared by Product Safety Labs. 43 p.

46913301 Carney, E.; Zablotny, C.; Quast, J.; et al. (2006) DIMTS : Two

- Generation Dietary Reproductive Toxicity Study in CD Rats. Project Number: 031007, 031007A, 031007A/2. Unpublished study prepared by Dow Chemical Co . 1661 p.

46913302 Carney, E.; Zablotny, C.; Johnson, K. (2006) DIMTS : One

- Generation Dietary Reproduction Toxicity Study in CD Rats. Project Number: 031007. Unpublished study prepared by Dow Chemical Co. 440 p.Docket Number EPA

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Page 62 of 79 47076601 Saghir, S.; Brzak, K.; Clark, A.; e t al. (2007) DIMTS Antifungal Agent: Pharmacokinetics and Metabolism in Fischer 344 Rats. Unpublished study prepared by Dow Chemical Co. 204 p.

47214601 Carney, E.; Zablotny, C.; Card, T.; et. al. (2007) DIMTS Antimicrobial Agent: Oral Gavage Developmental Toxicity Probe Study in New Zealand White Rabbits. Unpublished study prepared by The Dow Chemical Co. 149 p.

47242202 Carney, E.; Brooks, K.; Rasoulpour, R.; et al. (2007) DIMTS Antifungal Agent: Oral Gavage Developmental Toxicity Study in New Zealand Whi te Rabbits. Project Number: 061146. Unpublished study prepared by Dow Chemical Co. 337
p.

47292704 Saghir, S. (2007) DIMTS : De

- Iodinated Amical: Determination of Oral Absorption in Female CRL:CD(SD) Rats. Project Number: 061162. Unpublished study prepared by The Dow Chemical Co. 35 p.

47292705 Miksztal, M. (2007) DIMTS : Data Waiver for Chronic Toxicity and Carcinogenicity in Two Species. Unpublished study prepared by The Dow Chemical Co. 25 p.

47307306 Mecchi, M. (2007) Salmonella escherichia coli Mammalian

- Microsome Reverse Mutation Assay Preincubation Method with a Confirmatory Assay with DIMTS : Amended Final Report. Project Number: 6736/182, 29117/0/422OECD, 071075. Unpublished study prepared by Covance Laboratories, Inc. 72 p.

47338201 Carney, E.W.; Za blotny, C.L.; Johnson, K.A. (2003) DIMTS : 13

- Week Dietary Reproduction Probe Study in CD Rats. Project Number: 021121. Unpublished study prepared by Dow Chemical, USA. 200 p.

47338403 Miksztal, M. (2007) DIMTS : Acute Toxicity and Range Finding. Project Num ber: DR/0365/7838/060, 1073093, APR/76/377. Unpublished study prepared by Abbott Laboratories. 142 p.

48236901 Thomas, J.; Murray, J. (2010) DIMTS : 28

- Day Dermal Toxicity Study in Crl:CD(SD) Rats. Project Number: 091015. Unpublished study prepared by Dow C hemical Co. 325 p.

48264901 Hotchkiss, J.; Krieger, S.; Sura, R. (2010) DIMTS Antifugal Agent: 90

- Day Inhalation Toxicity Study in Crl:CD(SD) Rats. Project Number: 091053. Unpublished study prepared by The Dow Chemical Company. 412 p.

48293901 Durando, J. (2010) DIMTS Antimicrobial: Local Lymph Node Assay (LLNA) in Mice. Project Number: P327/DOW, 30508, 100171. Unpublished study prepared by Eurofins/Product Safety Laboratories. 41 p.

94039001 Trueblood, A. (1990) Angus Chemical Company Phase 3 Summary of MR ID 00050924. 21

- Day Subacute Dermal Toxicity in the Rabbit with DIMTS : Project No. 7820. Prepared by Pharmacopathics Research Labs., Inc. 29 p.Docket Number EPA

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Page 63 of 79 94039010 Trueblood, A. (1990) Angus Chemical Company Phase 3 Summary of MRID 00054961. Mutagencity [sic] Evaluat ion of DIMTS : Project No. 2683. Prepared by Litton Bionetics, Inc. 11 p.

94039011 Trueblood, A. (1990) Angus Chemical Company Phase 3 Summary of MRID 00160070. Mutagenicity of DIMTS in a Mouse Lymphoma Mutation Assay: Project #20989. Prepared by Litton Bio netics, Inc. 11 p.

94039012 Trueblood, A. (1990) Angus Chemical Company Phase 3 Summary of MRID 00160072. Evaluation of DIMTS in the Rat Primary Hepatocyte Unscheduled DNA Synthesis Assay: Project No. 20991. Prepared by Litton Bionetics, Inc. 10
p.

US EPA Guidance for Thyroid Assays in Pregnant Animals, Fetuses and Postnatal Animals, and Adult Animals. Internal guidance document, October 24, 2005. Office of Pesticide Programs, Health Effects Division, Washington, DC.Docket Number EPA

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Page 64 of 79 

# Appendix B Environmental Fate

Environmental Fa te and Transport Properties of DIMTS and its Degradation Products

Water and Sediment

Hydrolysis

DIMTS is stable to hydrolysis at pH 5, but degrades rapidly in pH 7 and 9 buffered solutions with linear half

- lives of 2.1

- 3.6 days. The major degradate was M IMPTS, whose concentrations did not decline in the study and reached 90

- 100 % of applied by the end of the study. The minor degradates MPTS and PTS O A were formed in the study (MRID 43008701 )

. Aqueous Photolysis

DIMTS degraded with a half

- life of 1.4 hou rs and no degradation occurred in the dark controls, which is consistent with the results of the hydrolysis study. Two significant degradates increased until the end of the study, including PTS O A which increased to 90 % by 24 hours, and MPTS, which increa sed to about 10 % ( MRID 47343001).

Octanol

- Water Partition Coefficient and Bioconcentration in Fish

The log P value for parent DIMTS (2.66) in Table 4 indicates that there is little potential for bioconcentration of fish, and the log P values for the deg radation compounds (

- 0.62 to 2.3) in Table 5 also indicate little potential for bioconcentration of the degradation compounds.

Aerobic Aquatic Metabolism

Aerobic aquatic metabolism data have not been submitted but are not required because the results from the hydrolysis and aerobic soil stud ies both indicate that parent DIMTS degrades to the MIMPTS and MPTS degradates

. Also, d ata on the persistence of DIMTS and MIMPTS under aquatic conditions are also available.

A na erobic Aquatic Metabolism

Under anaerob ic aquatic conditions, the total system, non

- linear half

- lives of parent DIMTS and the degradation compound MIMPTS were 9.6 and 11 days, respectively. Parent compound was associated more with water than sediment through 7 days and more in sediment afterwa rds. MIMPTS reached 16.2 % by 7 days, and then declined to <1 % by 3

- 6 months. MIMPTS was associated more in water than sediment for 60 days and then in equal portions thereafter. The degradation compound MPTS increased to 94.5 by 4

- 6 months, and was as sociated with water rather than sediment over the duration of the study. The degradation compound PTSOA did not reach significant levels in the study. Extractable residues were 23

- 31 % (0

- 14 days) and 16

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Page 65 of 79 % by 30

- 180 days, and non

- extractable residues never exceeded 2 %. Water soluble residues ranged from 68 to 85 % and volatiles did not exceed 0.8 % (MRID 42177201)

. Leaching from treated wood

In a submerged wood block study (E11

- 06, MRID 47375907), DIMTS leached from wood treated with 5.6

- 16 mg/cm 3 wi th maximum rates of 23.5

- 49.3 μg/cm 2 /day and cumulative rates of 309

- 413 μg/cm 2 . The percentages of leached DIMTS leached were 17.9 % for the 5.6 mg/cm 3 treatment rate, 9.9 for the 11.2 mg/cm 3 treatment rate, and a nd 8.1 % for the 16 mg/cm 3

treatment rat es

. Table B1 contains additional information on wood leaching.

Soil

Soil Leaching/Adsorption/Desorption Batch Equilibrium

Data on sorption of parent DIMTS to soil are required, along with the degradation products MIM P TS and MPTS are required because the se compounds can be present in significant amounts (>10 %) in the environment based on the results of both chemical and microbial degradation studies.

Aerobic Soil Metabolism

In aerobic soil (the top layer of non

- flooded soil), the non

- linear parent, MIMPT S, and MPTS half

- lives were 1.5, 32, and 53 days, respectively. The linear half

- life of MPTS was 173 days. PTSOA did not exceed 0.7 % in the study (MRID 41765405 ).

A na erobic Soil Metabolism

In the anaerobic soil metabolism study (flooded top layer of soil or the second layer of soil), the half

- lives of parent DIMTS were 1.7 and 4.2 days in aerobic (non

- flooded) and anaerobic (flooded soil) portions of the study, respectively. DIMTS was found in equal portions in water and sediment. MIMPTS was a major degradate with a half

- life of 21 days and was found predominantly in water. MPTS reached 81 % by the end of the study and was primarily found in water (MRID 41765406).

Soil Photolysis

Soil photolysis half

- lives of 13 days (linear) and 5.3 days (non

- linea r) were observed for parent compound. MIMPTS was stable in the dark control but degraded with a half

- life of 12.5 day in irradiated sample. Volatiles and non

- extractables were negligible (MRID 47323601)

. Fate and Transport in WWTP

Activated Sludge Sorptio n Isotherm

Data have not been submitted for activated sludge sorption isotherm (ASSI) for DIMTS but it is not required. The log P for DIMTS is 2.66 ( <3 ) , and a ccording to the Final 158W Rule, ASSIDocket Number EPA

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Page 66 of 79 data are not required if the log Kow is <3 ( Testnote 19 of Environmental Fate Requirements Table ).
Activated Sludge Biodegradation
In a ready biodegradability study (MRID 47338401, OECD 301F), DIMTS was not readily biodegradable at 28 and 67 mg/L because <60 % degraded within a 10

- day window after 10 % degradatio n in the 28

- day study. For the 67 mg/L test concent rat ion, t he amount of degradation by 10 days after 10 % degradation was 35

- 45 % % (28 mg/L data not provided) . D egradate identification was not conducted in this study. On the other hand, the reference compound, sodium benzoate, was readily biodegradable because >60 % degraded in a 10

- day window after 10 % degradation in the 28

- day study.
In another ready biodegradability study (MRID 47024601, OECD 301B), DIMTS was readily biodegradable because > 60 % de graded with in a 10

- day period after 10 % degradation occurred. In fact, DIMTS reached non

- detectable concentrations by two days in the study. However, it was only primarily biodegradable and not ultimately biodegradable at 0.05 and 0.5 mg/L because the t est material primarily formed terminal degradates other than CO 2 and water. For DIMTS residues, l imited mineralization to CO 2 and water (11

- 14 %) was observed in the study. The degradate MIMPTS (parent minus one iodine) was readily biodegradable at 0.05 mg/L but not at 0.5 mg/L. The half

- lives of the degradate MIMPTS (parent minus one iodine) were 1.2 day at 0.05 mg/L and 12.6 days at 0.5 mg/L , indicating that biodegradation is highly dependent on concentration . At 0.05 mg/L, MIMPTS declined to non

- signi ficant (<10 % of applied parent) concentrations by 7 days and was non

- detectable by 21 days. At 0.5 mg/L, MIMPTS declined to 15.2 % by study termination (29 days). The terminal degradate MPTS accumulated and reached 81

- 96 % of applied at 0.05 mg/L and 7 4 % at 0.5 mg/L by study termination. The recoveries at 0.05 mg/L were 98.5 + 5.5 %, and for 0.5 mg/L, were 112.4 + 4.7 %. The reference compound (sodium benzoate) degraded completely and was both readily biodegradable and ultimately biodegradable

In a Z ahn

- Wellens study (OECD 302B, OCSPP 835.3200), the biodegradation of the degradate methyl

- p

- tolyl sulfone (MPTS) was studied at 5 and 75 mg/L. Inherent biodegradation (including primary and ultimate) was measured. The reference compound (aniline) was ulti mately biodegradable based on the fact that 90 % of DOC was removed in four days, which is more than 70 % in 28 days. MPTS was not ultimately biodegradable because only about 48 % of DOC was removed in 28 days (MRID 47375909).
Activated Sludge Respiratio n Inhibition (ASRI)

DIMTS is not toxic to WWTP organisms when tested at >4.5 times its water solubility of <2 mg/L ( Table 4). In other words, based on results from an ASRI test, DIMTS was not observed to inhibit activated sludge microorganisms at test con centrations as high as 9 mg/L. The results of the positive controls were within 15 % of each other and the IC 50 value for the reference substance (sodium benzoate) was 12 mg/l, which is in the acceptable range of 5

- 30 mg/l (MRID 47373803). DIMTS would no t be expected to reach concentrations as high as 9 mg/L based on its solubility of <2 mg/L. Consequently, no further ASRI testing is needed for DIMTS or its degradates

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Page 67 of 79 Table B1. Environmental Fate Data Requirements for Diiodomethyl p

- tolyl sulfone

Da ta Requirement (OCSPP guideline unless specified) Study result Degradate results Reference (MRID unless specified) Status

Hydrolysis (835.2120) Stable at pH 5 Half

- lives of 2.1days at pH 7 and 3.6 days at pH 9 MIMPTS reached 90

- 100 % (end of study, 30 days) MPTS and PTS O A were minor degradates 43008701 Acceptable

Photodegradation in Water (835.2240) Half

- life of 1.4 hours PTS O A (90 %) and MPTS (10 %) Stable in dark control 47343001 Acceptable

Photodegradation on Soil (835.2410) Half

- life of 5.3 days MIMPTS half

- life of 12.5 days (irradiated) Stable in dark controls 47323601 Acceptable

Aerobic Soil Metabolism (835.4100) Half

- life of 1.5 day MIMPTS (32 days) MPTS (53 days) 41765405 Acceptable Anaerobic Soil Metabolism (835.4200) Half

- life of 1.7 day (aerobic phase) Half

- life of 4.2 days (anaerobic phase) MIMPTS half

- life of 21 days MPTS reached 81 % by the end of the study and did not decline

. 41765406 Acceptable

Anaerobic Aquatic Metabolism (835.4400) Half

- life of 9.6 days MIMPTS half

- life of 11 day s MPTS reached 95 % by end of study (180 days) 42177201 Acceptable

Aerobic Aquatic Metabolism (835.4300) No data N/A Required

Leaching

- Adsorption

Desorption (835.1230) No data No data Required for DIMTS

, MIM P T S, and MPTS Bioaccumulation in Fish (850.173 0) No data N/A Not required because log P <3 for parent and degradates Special Leaching Study (AWPA E11

- 06) Leaching rates

5.6 mg/cm 3 trt rate (1 % w/w) 23.5 (max) 19.1 (min) 20.4 (average) 19.9 (median) 309 (cumulative) 17.9 (% leached) N/A 47375907 Acc eptable Max, min, average, and median leaching rates in μg/cm 2 /day Cumulative leaching in μg/cm 2 Most relevant leaching rate is 5.6 mg/cm 3 treatment based on 1 % (w/w) treatment rate in study and 0.12

- 0.32 % AI treatment rate in Label Reg. No. 464

- 673 11.2 mg/cm 3 trt rate (2 % w/w) 34.4 (max) 19.4 (min) 23.3 (average) 22.7 (median) 351 (cumulative) 9.9 (% leached) 16 mg/cm 3 trt rate (3 % w/w)Docket Number EPA

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Page 68 of 79 49.3 (max) 21.1 (min) 25.8 (average) 23.5 (median) 413 (cumulative) 8.1 (% leached) Ready Biodegradabilit y (835.3110) DIMTS not readily biodegradable at 28 and 67 mg/L Not measured 47338401 Acceptable OECD 301F DIMTS was primarily biodegradable at 0.05 and 0.5 mg/L Not detectable after 2 days MIMPTS not detectable after 7 days in 0.05 mg/L DIMTS treatmen t MIMPTS detected throughout the 29

- day study at 0.5 mg/L DIMTS
treatment MIMPTS half

- lives of 1.2 day at 0.05 mg/L and 12.6 days at 0.5 mg/L

MPTS did not degrade in study 47024601 Supplemental OECD 301B

Inherent Biodegradability Zahn Wellens/EMPA Test (835.3200) No data MPTS (as parent compound) was not ultimately biodegradable at 5 and 75 mg/L 47375909 Acceptable

Inhibition of Sewage Sludge Respiration (850.3300) Not inhibitory at >9 mg/L (4.5X water solubility based on Table 5) N/A 47373803 Accept ableDocket Number EPA

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Page 69 of 79 Environmental Fate References

MRID 41765405. Cranor, W. (1990) Aerobic Soil Metabolism of ? carbon 14|

- Abbott

- 9248 ( DIMTS ): Lab Project Number: 36608. Unpublished study prepared by Analytical Bio

Chemistry Labs., Inc. 955 p.

MRID 41765406. Mads en, S.; Williams, M. (1990) Anaerobic Soil Metabolism of ?carbon 14|

- DIMTS : Lab Project Number: 38730. Unpublished study prepared by Analytical Bio

- Chemistry Labs., Inc. 461 p.

MRID 42177201. Madsen, S.; Williams, M. (1991) Anaerobic Aquatic Metabolism of ?carbon 14| DIMTS : Final Report: Lab Project Number: 38729. Unpublished study prepared by ABC Labs, Inc. 532 p.

MRID 43008701

. Williams, M.; Heim, L. (1993) Hydrolysis of DIMTS as a Function of pH at 25 (degrees) C: Lab Project Number: 40886. Unpublished study prepared by ABC Laboratories, Inc. 63 p.

MRID 47024601. Davis, J.; Erhardt, S. (2005) DIMTS : Determination of Biodegradability Using a Modified OECD 301B CO2 Evolution Test. Project Number: 041126. Unpublished study prepared by The Dow Chemical Com pany. 29 p.

MRID 47323601. Madsen, S.; Williams, M. (1991) Determination of the Photolysis Rate of (Carbon 14)

- DIMTS on the Surface of Soil. Project Number: 38727. Unpublished study prepared by ABC Laboratories, Inc. 691 p.

MRID 47338401. Gonsoir, S.J.; Stock, M.K.; Rivard, M.A. (2002) Evaluation of the Ready Biodegradability of DIMTS Preservative Using the OECD Method 301F: Manometric Respiratory Test. Project Number: 011091. Unpublished study prepared by Dow Chemical, USA. 29 p.

MRID 47343001. Williams , M.; Madsen, S.; Quinn, B. (1991) Determination of the Photolysis Rate of (Carbon 14)

- DIMTS in pH 5 Buffered Solution at 25 Degrees Celsius. Project Number: 38728. Unpublished study prepared by ABC Laboratories, Inc. 45 p.

MRID 47373803 . Gonsior, S.; Riv ard, M.; Stock, M. (2002) Activated Sludge, Respiration Inhibition Test (OECD 209) for DIMTS Preservative. Project Number: 01121 3. Unpublished study prepared b y Dow Chemical Co. 15 p.

MRID 47375909

. Gonsior, S.; Hales, C. (2007) Methyl

- P

- Tolylsulfone: Bio degradation in an Activated Sludge Die

- Away Study. Project Number: 071065. Unpublished study prepared by Dow Chemical, USA. 21 p.Docket Number EPA

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Page 70 of 79 U.S. EPA. May 8, 2013. Data Requirements for Antimicrobial Pesticides; Final Rule. Docket identification number EPA

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- 0110

. https://www.federalregister.gov/articles/2013/05/08/2013

- 10162/data

- requirements

- for

antimicrobial

- pesticides

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Page 71 of 79 

# Appendix C Ecotoxic ology Profile

Toxicity to Terrestrial Receptors

Birds

Based on studies in the a gency’s files, DIMTS appears to be practically nontoxic to birds when ingested on an acute or dietary basis

. It is not anticipated that any further studies in birds will be
req uired at this time.

C 1 Birds (Acute Oral Toxicity & Dietary Toxicity)

Species Chemical % Active Ingredient Endpoint Toxicity Category Satisfies Guidelines MRID

B obwhite quail Colinus virginianus ) Diiodomethyl
p

- tolyl sulfone (Acute Oral) 95 LD 50 > 2000 (mg ai/kg bw) Practically Non

Toxic Yes (core) 123643

Diiodomethyl
p

- tolyl sulfone (Dietary) 95 LD 50 = 5620 (ppm) Practically Non

Toxic Yes (core) 123642

Mallard duck ( Anas platyrhynchos) Diiodomethyl
p

- tolyl sulfone (Dietary) 95 LD 50 = 5620 (ppm) Practically Non

Toxic Yes (core) 124488

Mammals

Based on the results of mammalian studies conducted to meet human toxicity data requirements, diiodomethyl p

- tolyl sulfone exhibits low acute oral and acute dermal toxicity (Toxicity Category IV) , and high acute inhalation toxicity (Toxicity Category II). Diiodomethyl p

- tolyl sulfone is classified as an eye corrosive (Toxicity Category I). For dermal irritation, diiodomethyl p

- tolyl sulfone is a low irritant (Toxicity Category IV) and is not class ified as a dermal sensitizer. It is not anticipated that any further studies in mammals will be required to assess the ecological risk posed by DIMTS

. For further data refer to Appendix A.

Beneficial Insects

Per 40 CFR 158W, a honeybee acute contact study is typically required for chemicals labeled for use as wood preservatives. It is anticipated that an acute toxicity study in honeybees will be required to assess the risk posed by DIMTS to insect pollinators (see Guideline 850.3020)

.
Terrestrial Plants

Terrestrial plants are not expected to have significant exposure to DIMTS when used as directed. It is not anticipated that any studies in terrestrial plants will be required at this time.Docket Number EPA

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## Toxicity to Aquatic Receptors

Freshwater Fish

The agency requires higher tier testing based on a chemical’s properties and fate in the environment.

Diiodomethyl p

- tolyl sulfone is acutely toxic to freshwater organisms and forms soluble and persistent major degradates. As such, chronic toxicity data is required to gain a more complete understanding of the chemical’s toxicity in aquatic environments. The requirement for chronic toxicity data in freshwater fish will be satisfied by a fish early

- life stage study (see Guidelines 850.1400). Because DIMTS is highly susceptible t o reductive dehalogenation in aqueous solution

, the preferred experimental test substance is the major degradate, MIMPTS (pa rent minus one iodo group) degradate. The preferred freshwater test species is rainbow trout. This data is anticipated to be require d

.
C 2 Freshwater Fish and Amphibian Toxicity Data
Species Chemical % Active Ingredient Endpoint Toxicity Category Satisfies Guidelines MRID

Rainbow trout Oncorhynchus mykiss ) Diiodomethyl
p

- tolyl sulfone 97.7% 96

- h LC 50 = 66.7 (μg ai/L) Very highly toxic Supplemen

ta l 47234001

Diiodomethyl
p

- tolyl sulfone 95% 96

- h LC 50 = 130 (μg ai/L) Highly toxic Yes (core) 149730

Bluegill

su nfish Lepomi s macrochirus ) Diiodomethyl
p

- tolyl sulfone 95% 96

- h LC 50 = 750 (μg ai/L) Highly toxic Yes (cor e) 149731

Freshwater Invertebrates

The a gency requires higher tier testing based on a chemical’s properties and fate in the environment.

Diiodomethyl p

- tolyl sulfone is acutely toxic to freshwater organisms and forms soluble and persistent major degrad ates. As such, chronic toxicity data is required to gain a more complete understanding of the chemical’s toxicity in aquatic environments. The requirement for chronic toxicity data in freshwater invertebrates will be satisfied by an aquatic invertebrate li fe

- cycle study (see Guidelines 850.1300). Because DIMTS is highly susceptible to reductive dehalogenation in aqueous solution , the preferred experimental test substance is the major degradate, MIMPTS (pa rent minus one iodo group) degradate. The preferred f reshwater test species is Daphnia magna. This data is anticipated to be required

. C3 Freshwater Invertebrates Toxicity Data
Species Chemical % Active Ingredient Endpoint Toxicity Category Satisfies Guidelines MRID

Diiodomethyl
p

- tolyl sulfone 97.7% 48

- h EC 50 = 279 (μg ai/L) Highly toxic Yes (core) 47234002Docket Number EPA

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Page 73 of 79 Waterflea (Daphnia magna) Diiodomethyl
p

- tolyl sulfone 95% 48

- h EC 50 = 7,400 (μg ai/L) 4 Moderately Toxic Yes (core) 149729

Diiodomethyl
p

- tolyl sulfone 95% 48

- h EC = 50 71 (μg ai/L) 5 Very Highly Toxic Supplemen

tal 123644

Estuarine/Marine Fish

Acute toxicity testing with estuarine/marine organisms using the TGAI is required when an end

- use product is intended for direct application to the marine/estuarine environment or the acti ve ingredient is expected to reach this environment in significant concentrations because of its expected use and mobility. As such, the agency requires acute toxicity data in estuarine/marine fish for DIMTS ( see Guideline 850.1075 ). There are currently no acute toxicity data for diiodomethyl p

- tolyl sulfone in estuarine/marine fish. This data is anticipated to be required.

Estuarine/Marine Invertebrates

Acute toxicity testing in estuarine marine organisms using the TGAI is required when an end

- use produc t is intended for direct application to the marine/estuarine environment, or the active ingredient may reach the aquatic environment in significant concentrations as a result of leaching and environmental mobility, as in the use of DIMTS as a wood preserva tive. There are currently no acceptable acute toxicity data for estuarine/marine shrimp ( see Guideline 850.1035), or estuarine/marine mollusk ( see Guideline 850.1025) for dii odomethyl p

- tolyl sulfone. This data is anticipated to be required.

Aquatic Pla nts
Microphytes and Floating Vascular Macrophyte s
Acute toxicity testing in aquatic plants is required when an end

- use product is intended for direct application to the marine/estuarine environment, or the active ingredient may reach the aquatic environmen t in significant concentrations as a result of leaching and environmental mobility, as in the use of DIMTS as a wood preservative. There are currently no acceptable toxicity data for diiodomethyl p

- tolyl sulfone in vascular aquatic plants (see Guideline 85 0.4400)

, green algae (see Guideline 850. 4500 ) , or cyanobacteria (see Guideline 850.4550) . This data is anticipated to be required

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Page 74 of 79 Ecot oxicology References for Appendix C
Fink, R.; Beavers, J.; Grimes, J.; et al. (1978) Acute Oral LD50

-- Bobwhite Qua il: A

- 9248: Project No. 161

- 104. Final rept. (Unpublished study received Sep 7, 1979 under 275

- 21; prepared by Wildlife International Ltd. and Washington College, submitted by Abbott Laboratories, North Chicago, IL; CDL:240936

- C)
Trueblood, A. (1990) Angus Chemical Company Phase 3 Summary of MRID 00123643. Acute Oral Toxicity Study of DIMTS in Bobwhite Quail: Project #161

- 104. Prepared by Wildlife International, Ltd. 13 p.

Fink, R.; Beavers, J.; Joiner, G.; et al. (1978) Eight

- day Dietary LC50

-- Bobwhite Qua il: A

- 9248: Project No. 161

- 105. Final rept. (Unpublished study received Sep 7, 1979 under 275

- 21; prepared by Wildlife International Ltd. and Washington College, submitted by Abbott Laboratories, North Chicago, IL; CDL:240936

- B)

Fink, R.; Beavers, J.; Gri mes, J.; et al. (1978) Eight

- day Dietary LC50

-- Mallard Duck: A

- 9248: Project No. 161

- 106. Final rept. (Unpublished study received Sep 7, 1979 under 275

- 21; prepared by Wildlife International Ltd. and Washington College, submitted by Abbott Laboratories, No rth Chicago, IL; CDL:240936

- A)

Trueblood, A. (1990) Angus Chemical Company Phase 3 Summary of MRID 00123642. Eight

Day Dietary Toxicity Study of DIMTS in Bobwhite Quail: Project #161

- 105. Prepared by Wildlife International Ltd. 12 p.

Trueblood, A. (1990) A ngus Chemical Company Phase 3 Summary of MRID 00124488. Eight

Day Dietary Toxicity Study of DIMTS in the Mallard Duck; Project No. 161

- 106. Prepared by Wildlife International, Ltd. 12 p.

Forbis, A.; Georgie, L.; Burgess, D. (1984) Acute Toxicity of Ami

- ca l 48 to Rainbow Trout (Salmo gairdneri): Static Acute Toxicity Report #31946. Unpublished study prepared by Analytical Bio

- chemistry Laboratories, Inc. 60 p.

Marino, T.; McClymont, E.; Yaroch, A. (2007) DIMTS Antifungal Agent: An Acute Toxicity Study with the Rainbow Trout, Oncorhynchus mykiss. Unpublished study prepared by The Dow Chemical Company. 42 p.
Hunziker, R.W. (2007) Estimation of Water Solubility Limit, Octanol

- Water Partitioning Constant, and Aquatic Toxicity of Monoiodo

- p

- methyltolysulphone an d p

Methyltolylsulphone Which Are Breakdown Products of the Biocidal Active di

- iodo

methyl

- para

- tolyl

- sulphon (DIMTS). Project Number: DR/0122/8542/003. Unpublished study prepared by Dow Chemical Europe and Dow Chemical Co. 16 p.
Miksztal, M. (2007) DIMTS : Acute Toxicity and Range Finding. Project Number: DR/0365/7838/060, 1073093, APR/76/377. Unpublished study prepared by Abbott Laboratories. 142 p.Docket Number EPA

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Page 75 of 79 Bollmeier, A. (1990) Angus Chemical Company Phase 3 Summary of MRID 00149731. Acute Toxicity of DIMTS to Blu egill Sunfish: Static Acute Toxicity: Report No. 31945. Prepared by ABC Labs. Inc. 10 p.
Bollmeier, A. (1990) Angus Chemical Company Phase 3 Summary of MRID 00149730. Acute Toxicity of DIMTS to Rainbow Trout: Static Acute Toxicity: Report No. 31946. Prepar ed by ABC Labs., Inc. 1 p.
Suprenant, D.; Ziencina, M. (1978) Acute Toxicity of A

- 9248 to the Water Flea (Daphnia
magna ): Report #BW

- 78

- 9

- 308. (Unpub lished study received Sep 7, 1979 under 275

- 21; prepared by EG & G, Bionomics, submitted by Abbott Laborato ries, North Chicago, IL; CDL:240936

- D)
Forbis, A.; Burgess, D.; Georgie, L . (1984) Acute Toxicity of DIMTS to Daphnia magna: Static Acute Toxicity Report # 31947. Unpublished study prepared by An alytical Biochemistry Laborato ries, Inc. 38 p.

Marino, T.; Ya roch, A.; Arnold, B.; et al. (2007) DIMTS Antifungal Agent: An Acute Toxicity Study with the Daphnid, Daphnia magna. Unpublished study prepared by Dow Chemical Co. 42 p.
Bollmeier, A. (1990) Angus Chemical Company Phase 3 Summary of MRID 00149729. Acute To xicity of DIMTS to Daphnia magna: Static Acute Toxicity: Report No. 31947. Prepared by ABC Labs., Inc. 1 p.
Hamlin, J. (1972) Report to: Abbott Laboratories, Chemical Division: Four

- Day Static Fish Toxicity Studies with DIMTS and Amical 77 in Rainbow Trout and Bluegills: IBT No. A1244. (Unpublished study received Mar 9, 1972 under 275

- 22; prepared by Industrial Bio

- Test Laboratories, Inc., submitted by Abbott Laboratories, North Chicago, Ill.; CDL:002251

- H)
Kirk, H.; Staley, J.; McClymont, E.; et al. (2002) DIMTS Antimicrobial: Growth Inhibition Test with the Freshwater Green Alga. Selenastrum capricornutum. Project Number: 011189. Unpublished study prepared by Dow Chemical Co. 43 p.Docket Number EPA

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Page 76 of 79 

# Appendix D Screening Level Down

- the

Drain Analysis

The Down

- the

- Drain (DtD) modu le of E

- FAST (Exposure and Fate Assessment Screening Tool), [version 2] was used to screen for the potential for aquatic organisms downstream of domestic wastewater treatment plants to be exposed to DIMTS and its degradates. The Down

- the

- Drain module uses daily per capita release of household wastewaters, stream dilution factors, and wastewater treatment plant removal efficiency to provide both high

- end and median (average) time

- averaged surface water concentrations of chemicals discharged by domestic waste water treatment plants. The high

- end scenario uses surface water concentrations downstream of domestic wastewater treatment plants based on the 10 th percentile stream dilution factor (SDF); the average scenario uses surface water concentrations based on th e 50 th percentile SDF. SDF is defined as the ratio of the stream flow downstream of a wastewater treatment plant to the wastewater treatment plant flow. Inputs used to run the DtD module included concentrations of concern (COCs) for aquatic organisms, perc ent removal during wastewater treatment, and hypothetical wastewater treatment plant influent volumes.

The results of the DtD module are expressed as number of days of exceedance of COCs for aquatic organisms. COCs are grouped into 3 categories: acute, en dangered/listed, and chronic. Acute COCs for freshwater fish and invertebrates were derived by dividing LC 50 values for freshwater organisms by 2. Endangered/listed COCs for freshwater fish and invertebrates were derived by dividing LC 50 values by 20. E C 50 values for plants were used to establish acute COCs for plants. NOAEC values for plants were used to establish endangered/listed COCs for plants. Chronic COCs for freshwater fish and invertebrates are based on NOAEC values. For acute and endangered listed COCs, there may be potential concern for freshwater organisms if the COC is exceeded for 1 day or more. For chronic COCs, there may be potential concern for freshwater organisms if the COC is exceeded 20 days or more. In the absence of data on rem oval of DIMTS during wastewater treatment, no removal of DIMTS during wastewater treatment was assumed.

The Down

- the

- Drain module was first run using a high

- end scenario to determine whether the model predicted exceedances of concentrations of concern. If the high

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Page 77 of 79 

# Appendix E Product Chemistry

The product chemistry information for parent DIMTS relevant to risk assessment is summarized in Table E1, while the product chemistry information for the degradates m onoiodo

- p

methyltolylsulfone (MIM P TS , parent compound minus one iodo group) , methyl

- p

- tolylsulfone (MPTS , parent compound minus both iodo groups ) and p

- toluene sulfonic acid (PTSOA , parent compound minus both iodo groups and a methyl group with added hydroxyl group ) are summarized in Table E2

.
Table E1

– Physical

- Chemical and Environmental Fate Properties for Parent DIMTS

Guideline No. P arameter DIMTS Reference (MRID unless spec ified) Comments

830.7050 UV/Visible Absorption Max sorption at 288 nm, some tailing through 409 nm 47234003

830.7370 Dissociation c onstant (pKa) Not applicable 48511201

830.7550 Octanol

- water partition coefficient at 25 o C (Log K ow ) 2.66 42177202

830. 7840 Solubility in water (mg/L) <2 47373801 830.7950 Vapor pressure (mmHg) 4.9 x 10

- 7 47373801

None Henry's l aw c onstant at 25 o C (atm

- m 3 /mol) 1.4 x 10

- 7 Calculated

atm

- m 3 /mol = atmosphere cubic meter per mole; o C = degrees Celsius; mg/L = milligrams pe r liter; mmHg = millimeters of mercury;

Table E2

– Physical

- Chemical and Environmental Fate Properties for Monoiodo

- p methyltolyls ulfone (MIMPT S), methyl

- p - tolylsulfone (MPTS), and p

- toluene sulfonic acid (PTSOA) Degradates

Guideline No. Parameter Monoi odo

- p methyltolylsulfone (MIM P TS) Methyl

- p - tolyl sulfone ( MPTS ) P

- toluene sulfonic acid (PTSOA) Reference (MRID unless specified) Comments

None Structure None

None Description Parent minus 1 iodine Parent minus two iodines Hydroxylated,

once

- demeth ylated MPTS None

None PC Code None None None Not applicable

None CAS No. 37891

- 96

- 6 59203

- 01

- 9 104

- 15

- 4 Dow MSDS (MIM P TS) O
S
O H 3 C I O
S O H

3 C

C H

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Page 78 of 79 Guideline No. Parameter Monoi odo

- p methyltolylsulfone (MIM P TS) Methyl

- p - tolyl sulfone ( MPTS ) P

- toluene sulfonic acid (PTSOA) Reference (MRID unless specified) Comments Chemical Book ( MPTS )

None Smiles code O=S(=O)(c(ccc(c1)C) c1)C(I) O=S(=O)(c(ccc(c1)C) c1)C O=S(O)(=O)(c(ccc( c1)C)c1) EPI

- WEB 4.11

None Molecular formula C 8 H 9 IO 2 S C 8 H 10 O 2 S C 7 H 8 O 3 S EPI

- Web 4.11

None Molecular weight 296.12 170.23 172.20 EPI

- WEB 4.11

830.7050 UV/Visible Absorption No data No data No data Similar to parent

830.7370 Dissociation constant (pKa) Not applicable Not appli cable Not applicable Similar to p arent

830.7550 Octanol

- water partition coefficient at 25 o C (Log K ow ) 2.3 1.94

- 0.62 47338402 (MIM PT S and MPTS) EPI

- WEB 4.11 (PTSOA)

830.7840 Solubility in water (mg/L) 140.4 1

, 352 6.2 x 10 5 47338402 (MIM PT S and MPTS) EP I

- WEB 4.11 (PTSOA)

830.7950 Vapor pressure (mmHg) 2.3 x 10

- 5 2 x 10

- 3 2.9 x 10

- 6 EPI

- WEB 4.11

None Henry's law constant at 25

o C (atm

m 3 /mol) 6.4 x 10

- 8 3.3 x 10

- 7 1.1 x 10

- 12 Calculated

atm

- m 3 /mol = atmosphere cubic meter per mole; o C = degrees Celsius ; mg/L = milligrams per liter ; mmHg = millimeters of mercury.Docket Number EPA

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Page 79 of 79 Product Chemistry References

Chemical Book. 2010. METHYL P

- TOLYL SULFONE

. http://www.chemicalbook.com/Che micalProductProperty_EN_CB8463935.htm

Dow MSDS. August 11, 2011. Material Safety Data Sheet: DIMTS

. http://msdssearch.dow.com/publishedliteratured owcom/dh_0819/0901b80380819eaa.pdf?filepat h =..

EPI

- WEB 4.11. 2012. http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm

MRID 42177202

. Laster, W.; McGowan, N. (1991) Octanol/ Water P artition Coefficient of DIMTS : Final Report: Lab Project Number: 39209. Unpublished study prepared by ABC Labs, Inc. 377 p.

MRID 47234003. Lopez, A. (2007) Determination of UV/Visible Absorption Characteristics of DIMTS Antifungal Agent. Project Number: 1 654W. Unpublished study prepared by PTRL West, Inc. 29 p.

MRID 47373801

. Sinning, D. (2003) Physical and Chemical Characteristics of DIMTS : Melting Point, Boiling Point, Density, Water Solubility, and Vapor Pressure. Project Number: 2310/16, 020030. Unpub lished study prepared by Case Consulting Laboratories, Inc. 12 p.

MRID 47338402

. Hunziker, R.W. (2007) Estimation of Water Solubility Limit, Octanol

- Water Partitioning Constant, and Aquatic Toxicity of Monoiodo

- p

- methyltolysulphone and p

Methyltolylsulpho ne Which Are Breakdown Products of the Biocidal Active di

- iodo

- methyl

para

- tolyl

- sulphon (DIMTS). Project Number: DR/0122/8542/003. Unpublished study prepared by Dow Chemical Europe and Dow Chemical Co. 16 p.

MRID 47373801

. Sinning, D. (2003) Physical an d Chemical Characteristics of DIMTS : Melting Point, Boiling Point, Density, Water Solubility, and Vapor Pressure. Project Number: 2310/16, 020030. Unpublished study prepared by Case Consulting Laboratories, Inc. 12 p.

MRID 48511201

. O'Connor, B.; Woolley , S. (2011) DIMTS : Determination of Dissociation Constants in Water. Project Number: 41005025, 24P/2010/030, GLP/2011/024. Unpublished study prepared by Harlan Laboratories, Ltd. 13 p.